Exhibit 10.85
Portions of this Exhibit have been omitted pursuant to a request for
confidential treatment. The omitted portions, marked by a * and [ ], have
been separately filed with the Commission.
AMENDMENT NO. 1 TO MASTER CONSULTING AGREEMENT
The Master Consulting Agreement, by and between Interneuron and Quintiles,
consisting of one (1) page, dated 3 July, 1996, is hereby amended as follows:
(1) The following Attachments shall be made a part of the Master Consulting
Agreement, to wit:
ATTACHMENT NO. 1
SCOPE OF WORK (PROTOCOL NO. [_________]) *
ATTACHMENT NO. 2
PROJECT BUDGET (PROTOCOL NO. [_________]) *
ATTACHMENT NO. 3
PAYMENT SCHEDULE (PROTOCOL NO. [_________]) *
QUINTILES, INC. INTERNEURON PHARMACEUTICALS
BY /s/ X.X. XXXXXXXX BY /s/ XXXXX X. XXXXXX
---------------------------- ----------------------------
X. X. XXXXXXXX, DR. P.H.
VICE PRESIDENT, TITLE PRESIDENT
CONTRACTS MANAGEMENT & PLANNING -------------------------
DATE 3 JULY 1996 DATE JULY 12, 1996
-------------------------- --------------------------
FEDERAL ID # 00-0000000
The information below marked by * and [ ] has been omitted pursuant to a request
for confidential treatment. The omitted portion has been separately filed with
the Commission.
ATTACHMENT NO. 1
SCOPE OF WORK
PROTOCOL NO. [_________] *
TABLE OF CONTENTS
SECTION PAGE
I. SERVICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Service Checklist
II. OVERALL PROJECT MANAGEMENT . . . . . . . . . . . . . . . . . . . . . 6
Overall Program and Study Strategy
Weekly Progress Reports
Project Team Meetings
Quality Assurance
III. STUDY DOCUMENT DEVELOPMENT . . . . . . . . . . . . . . . . . . . . . 8
Protocol Development
Informed Consent Form
Case Report Form
Study Reference Manual
IV. PROJECT INITIATION . . . . . . . . . . . . . . . . . . . . . . . . . 9
Investigational site Recruitment and Qualification
Regulatory Documents
Study Coordinator Training Meetings
Central Laboratory Services
Study Drug Management
Investigator Site Agreements
V. MANAGEMENT OF THE CLINICAL TRIAL . . . . . . . . . . . . . . . . . .12
Initiation Visits
Interim Monitoring Visits
Study Close-out Visits
Clinical Monitoring Communication
Communications with Sites
-2-
The information below marked by * and [ ] has been omitted pursuant to a request
for confidential treatment. The omitted portion has been separately filed with
the Commission.
SECTION PAGE
VI. MEDICAL MONITORING . . . . . . . . . . . . . . . . . . . . . . . . .15
Medical Support
Serious Adverse Event (SAE) and Expeditable AE Reporting
Expeditable AE Workflow
FDA Reporting
Drug Safety Databases
Drug Safety Procedures
VII. CLINICAL DATA MANAGEMENT . . . . . . . . . . . . . . . . . . . . . .17
Data Flow
Data Review Procedures
Programming
Data Entry/Optical Xxxx Recognition
Data Clarification with the Investigative Site
Quality Assurance
Adverse Event/Concomitant Medication Coding
Database Audit
VIII. BIOSTATISTICAL ANALYSIS. . . . . . . . . . . . . . . . . . . . . . .19
Statistical Analysis Plan
Final Analysis
Final Study Report
EXHIBIT NO. 1 - Quintiles Laboratories Limited, Proposal For Central Laboratory
Services
-3-
The information below marked by * and [ ] has been omitted pursuant to a request
for confidential treatment. The omitted portion has been separately filed with
the Commission.
Quintiles agrees to provide to Interneuron Project Management, Clinical,
Medical, Data Management, Statistical, Quality Assurance, and Central Laboratory
Services for the Citicoline trial to be conducted under Protocol No.
[_______________________________] *
Assumptions are based on the information provided to Quintiles in the
Interneuron Protocol No. [________________________] Interneuron's letter dated
May 7, 1996; and the *
Interneuron-Quintiles meeting in Cambridge, MA, on May 24, 1996.
I. SERVICES
--------------------------------------------------
STUDY SITES [______________________
______________________]
--------------------------------------------------
PATIENTS [_____________________]
[_____________________]
--------------------------------------------------
CRF PAGES
[_______________ [__]
________________ [__]
________________] [__]
--------------------------------------------------
TIME LINE
[_____________ [________]
______________ [________]
______________ [________]
______________ [________]
______________ [________]
______________ [________]
_____________] [________]
--------------------------------------------------
STUDY DURATION [________]
--------------------------------------------------
VISITS
[________] [________]
[________] [________]
[________] [________]
--------------------------------------------------
-4-
The information below marked by * and [ ] has been omitted pursuant to a request
for confidential treatment. The omitted portion has been separately filed with
the Commission.
--------------------------------------------------
INTERIM MONITORING [______________________
FREQUENCY _______________________
Frequency _______________________
______________________]
Source Document Review [________]
--------------------------------------------------
ESTIMATED NUMBER OF SAES [________]
--------------------------------------------------
STATISTICAL ANALYSIS
[________________ [________]
_________________ [________]
_________________ [________]
_________________] [________]
--------------------------------------------------
SERVICE CHECKLIST
--------------------------------------------------------------------------------
--------------------------------------------------------------------------------
ACTIVITY INTERNEURON QUINTILES
--------------------------------------------------------------------------------
PROJECT MANAGEMENT X
STUDY START-UP
[_____________________________] X
[_____________________________] X
[_____________________________] X
[_____________________________] X
[_____________________________] X
[_____________________________] X
[_____________________________] X X
[_____________________________] X
[_____________________________] X
[_____________________________] X
[_____________________________] X
-5-
The information below marked by * and [ ] has been omitted pursuant to a request
for confidential treatment. The omitted portion has been separately filed with
the Commission.
--------------------------------------------------------------------------------
ACTIVITY INTERNEURON QUINTILES
--------------------------------------------------------------------------------
[_____________________________] X
[_____________________________] X
[_____________________________] X
[_____________________________] X
[_____________________________] X
[_____________________________] X
[_____________________________] X
[_____________________________] X
[_____________________________] X
[_____________________________] X X
[_____________________________] X
GCP AUDITS X
CLINICAL MONITORING
[_____________________________] X
[_____________________________] X
[_____________________________] X
[_____________________________] X
[_____________________________] X
[_____________________________] X
MEDICAL MANAGEMENT
[_____________________________] X
[_____________________________] X
[_____________________________] X
[_____________________________] X
DATA MANAGEMENT
[_____________________________] X
-6-
The information below marked by * and [ ] has been omitted pursuant to a request
for confidential treatment. The omitted portion has been separately filed with
the Commission.
--------------------------------------------------------------------------------
ACTIVITY INTERNEURON QUINTILES
--------------------------------------------------------------------------------
[_____________________________] X
[_____________________________] X
[_____________________________] X
[_____________________________] X
[_____________________________] X
[_____________________________] X
BIOSTATISTICS
[_____________________________] X
[_____________________________] X
[_____________________________] X
[_____________________________] X
OTHER ACTIVITIES
[_____________________________] X X
--------------------------------------------------------------------------------
--------------------------------------------------------------------------------
--------------------------------------------------------------------------------
--------------------------------------------------------------------------------
--------------------------------------------------------------------------------
--------------------------------------------------------------------------------
--------------------------------------------------------------------------------
--------------------------------------------------------------------------------
--------------------------------------------------------------------------------
-7-
The information below marked by * and [ ] has been omitted pursuant to a request
for confidential treatment. The omitted portion has been separately filed with
the Commission.
II. OVERALL PROJECT MANAGEMENT
OVERALL PROGRAM AND STUDY STRATEGY
Quintiles has assigned a Project Manager to oversee this study. This individual
will be Interneuron's advocate within Quintiles, taking primary responsibility
for communications with Interneuron; providing day-to-day direction to the
Quintiles' project team; and communicating progress, issues, and problems with
proposed resolutions to Interneuron as needed. The Project Manager will
communicate the project goals, deadlines, and strategy to team members on a
timely basis ensuring that any questions will be addressed by the appropriate
resource within Quintiles. Changes to the scope of work, issues surrounding
scheduled activities, and other significant activities that affect the
administration of the contract will be monitored by the Project Manager.
The Project Manager will direct this project each step of the way, ensuring
adherence to schedules and to the project's scientific requirements. The
Project Manager will coordinate skilled technical Project Team members as
dictated by the scope of the project.
WEEKLY PROGRESS REPORTS
On a weekly basis, Quintiles will provide Interneuron with a study progress
report. The Quintiles' Administrative Management System (QAMS-TM-) will be
utilized to record study status information. QAMS-TM- will be programmed to
include the following information:
[_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________]
Custom features or special reports may be requested by Interneuron, but are not
included as part of the costs for this scope of work. Required reports will be
identified at the start of the study so that the system design is operational
prior to site initiation.
PROJECT TEAM MEETINGS
-8-
The information below marked by * and [ ] has been omitted pursuant to a request
for confidential treatment. The omitted portion has been separately filed with
the Commission.
Key Quintiles Project Team members attended a joint Interneuron-Quintiles
face-to-face interdisciplinary team meeting at Quintiles' offices in Cambridge,
Massachusetts, on May 24, 1996, to address various issues related to the
project. The purpose of this meeting was to discuss primary points of contact
within each Company, reiterate project reporting requirements, review the
project schedule, and clarify other ad hoc issues.
Quintiles' CRAs assigned to this project will be available to meet with
Interneuron via teleconference prior to study initiation to discuss the project
in detail. The Quintiles' Project Team will hold internal team meetings on a
weekly basis (more or less frequently as project status dictates) to review the
progress of the project.
In addition to these internal team meetings, Quintiles' Project Manager will
participate in Project Team meetings with Interneuron throughout the course of
the project. These meetings will ensure the communication necessary to meet
study goals and successful completion of the project. Key members of Quintiles'
Project Team will attend these meetings. Quintiles assumes that these meetings
will occur primarily as teleconferences between Interneuron and Quintiles.
Occasional video teleconferences or face-to-face Project Team Meetings may also
occur either at Interneuron's or at Quintiles' offices.
[_______________________________________________________________________________
________________________________________________________________________________
____________]
At Interneuron's request, Quintiles' Clinical Monitoring Team assigned to this
project attended a training meeting presented in conjunction with the National
Stroke Association's conference in Colorado Springs, CO, on June 5, 1996.
[_______________________________________________________________________________
________________________________________________________________________________
___________________________________]
QUALITY ASSURANCE
The QA team will oversee all quality assurance activities, particularly with
regard to compliance to regulatory guidelines and company policies and
procedures, and to ensure that the formal quality control process is working as
intended within each business unit.
GCP AUDITS
-9-
The information below marked by * and [ ] has been omitted pursuant to a request
for confidential treatment. The omitted portion has been separately filed with
the Commission.
[_______________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
______________]
[_______________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
______________]
[_______________________________________________________________________________
________________________________________________________]
III. STUDY DOCUMENT DEVELOPMENT
PROTOCOL DEVELOPMENT
Interneuron will be responsible for preparing and providing to Quintiles a
final, approved protocol for this study. Quintiles anticipates the study
protocol will be in final form, requiring no revisions.
INFORMED CONSENT FORM
Interneuron will develop a model document with standard informed consent
language that will be mandatory for every site. Interneuron will be responsible
for all regulatory review and customization of the forms to meet local
regulations.
CASE REPORT FORM PREPARATION
Quintiles will develop Optical Xxxx Recognition (OMR) CRFs for this project.
Representatives from Quintiles' Clinical, Biostatistical, Medical, and Clinical
Data Management Departments will collaborate with Interneuron to determine the
CRF design that will provide efficient and complete collection of the necessary
data for the
-10-
The information below marked by * and [ ] has been omitted pursuant to a request
for confidential treatment. The omitted portion has been separately filed with
the Commission.
study. Quintiles will design the CRFs according to Interneuron's
specifications. Quintiles has assumed that two (2) draft sets of the CRFs will
be provided to Interneuron for review and comment. Quintiles will incorporate
Interneuron's comments and generate a master set of CRFs, which will be
submitted to Interneuron for final review and approval. [_______________________
________________________________________________________________________________
________________]
STUDY REFERENCE MANUAL
Quintiles will develop a Study Reference Manual for use as a training and
reference tool by the Investigators. This manual will provide detailed
instructions on [_______________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
____] Sections of the manual will
include:[_______________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
__________________________] The manual will also serve as a consistent training
guide for each site as new site personnel are added during the conduct of the
study. As necessary, manuals will be kept current with updated sections
regarding any modifications to on-site study conduct.
IV. PROJECT INITIATION
INVESTIGATIONAL SITE RECRUITMENT AND QUALIFICATION
Quintiles will collaborate with Interneuron to identify [__________]
investigational sites to be qualified for consideration in this study.
Interneuron will provide Quintiles with the names, addresses, and telephone
numbers of the proposed Investigators for this study.
Quintiles will screen potential Investigators by telephone in order to ascertain
the Investigator's interest and ability to conduct this clinical trial. Once
interest and ability have been established, and a Confidential Disclosure
Agreement has been executed, the protocol and supporting documents will be
forwarded to the Investigator for review. Each site will be evaluated by a
member of Quintiles' monitoring staff through another telephone contact. During
this call the protocol will be discussed in depth along with other issues
necessary to determine a site's ability to participate in
-11-
The information below marked by * and [ ] has been omitted pursuant to a request
for confidential treatment. The omitted portion has been separately filed with
the Commission.
the study,
[_______________________________________________________________________________
________________________________________________________________________________
______] Final site qualification will be confirmed in conjunction with the
site's initiation visit Quintiles anticipates that many of the sites recommended
by Interneuron for participation in this study will be sites with whom
[_______________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
________________________]
Interneuron will maintain the final approval of Investigator(s) selected by
Quintiles.
REGULATORY DOCUMENTS
Quintiles will be responsible for collecting from each site the regulatory
documents required for the study. Quintiles will obtain the clinical trial
documentation required by 21 CFR Section 312.53(c)(1),(2),(3). Quintiles will
transmit any other trial materials requested by Interneuron to each
Investigator. Quintiles' Regulatory Services staff will review all Investigator
documentation, including all informed consent forms, prior to submission to
Interneuron. When the Investigator is required to utilize a local IRB,
Quintiles will assist, as necessary, to coordinate the approval process.
[_______________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
_____________________________]
-12-
The information below marked by * and [ ] has been omitted pursuant to a request
for confidential treatment. The omitted portion has been separately filed with
the Commission.
Quintiles will forward all required documentation to Interneuron for submission
to the FDA or other regulatory agency.
STUDY COORDINATOR TRAINING MEETINGS
Quintiles will plan, manage, and conduct meetings to provide project-specific
training to study coordinators for this project. Quintiles' responsibilities
will include preparing meeting presentations on relevant topics in conjunction
with Interneuron. Major agenda points to be covered by Quintiles and
Interneuron staff for these meetings, as well as other items, will be developed
and distributed prior to each meeting.
[_______________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
_______________________]
CENTRAL LABORATORY SERVICES
Quintiles Laboratories, Ltd. (QLAB) will be utilized for all centralized
clinical laboratory analyses and will interact with Quintiles with regard to
laboratory data transfers and patient laboratory accountability issues.
[_______________________________________________________________________________
________________________________________________________________________________
_____________________________________________]
QLAB will provide laboratory reports both electronically and in hard copy on a
routine basis.
[_______________________________________________________________________________
________________________________________________________________________________
_____________________________________________]
STUDY DRUG MANAGEMENT
[_______________________________________________________________________________
________________________________________________________________________________
_____________________________________________]
Quintiles will be responsible for drug accountability at the study sites, return
of unused drug to Interneuron, and drug supply reconciliation.
-13-
The information below marked by * and [ ] has been omitted pursuant to a request
for confidential treatment. The omitted portion has been separately filed with
the Commission.
INVESTIGATOR SITE AGREEMENTS
Quintiles will negotiate and sign a Clinical Study Agreement with each of the
[___________] Principal Investigators/investigational sites for participation in
the study. The Agreements will include a grant and payment schedule using
guidelines provided by Interneuron. The form of this Agreement will be approved
in advance by Interneuron and any significant deviation from the approved,
standard contract will require Interneuron's written approval.
[____________________________________________
________________________________________________________________________________
___________]
Quintiles will assist Interneuron in formulating an equitable Investigator grant
and standard payment scheduled. Quintiles' estimated costs for this activity
assumes one standard payment schedule for all Investigators participating in the
study. Should Interneuron wish to offer greater flexibility to Investigators,
costs for payment administration will increase as payment schedule exceptions
are made.
Quintiles will track patient enrollment, discontinuation, and completion.
Periodically, a listing will be produced that describes the amounts due and
authorized to each Investigator according to the signed Clinical Study
Agreements. This listing will be accessed by Quintiles' Finance Department who
will prepare checks for each Principal Investigator/investigational site. These
checks will be signed, recorded, and distributed to the Principal
Investigator/investigational site. A record of disbursement will be provided to
Interneuron on a regular basis.
V. MANAGEMENT OF THE CLINICAL TRIAL
Quintiles monitors qualified by experience and training will perform the
monitoring responsibilities for this study.
Quintiles will assign a Lead CRA who will work with a Senior Clinical Project
Advisor to develop and coordinate the monitoring plan for this study. The
Project Advisor will have an ongoing role in clinical operations for the
project, participating in internal clinical group meetings and supporting the
Lead CRA in the management of clinical operation activities. The Lead CRA will
be responsible for coordinating the clinical monitoring team and will have
direct reporting responsibilities to the Project Manager.
[_______________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
_________]
-14-
The information below marked by * and [ ] has been omitted pursuant to a
request for confidential treatment. The omitted portion has been separately
filed with the Commission.
INITIATION VISITS
Quintiles' monitors will perform a comprehensive site initiation visit to each
of the investigational sites. The Quintiles' monitor will meet with the site
Investigator and study site personnel to assure compliance with protocol
procedures and CRF completion. Drug shipment will be coordinated with the
initiation visit, and verification of drug inventory and dispensing procedures
will be reviewed. A complete review of the site's regulatory file will be
performed. This visit will confirm that the site is qualified to participate in
the study and ensure that regulations and documentation for the project are
understood and that all forms are completed correctly by the Investigator and
study site coordinator.
INTERIM MONITORING VISITS
[_______________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
_________]
[_______________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
_________]
[_______________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
_________]
Data queries generated as a result of data entry and review requiring on-site
resolution will be grouped by site and forwarded to the responsible monitor for
resolution at the next scheduled visit.
Quintiles' budget assumes that all study supplies (including study drug) will
reside at the investigational site and all monitoring for each site will take
place at one location. The need to monitor any additional locations will be
determined on a site-by-site basis
[_______________________________________________________________________________
_______________________________________________________________________________]
-15-
The information below marked by * and [ ] has been omitted pursuant to a request
for confidential treatment. The omitted portion has been separately filed with
the Commission.
STUDY CLOSE-OUT VISITS
Quintiles will perform a study closeout visit to each of the sites participating
in this project.
[_______________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
_____________]
CLINICAL MONITORING COMMUNICATION
Quintiles will conduct [_______] monitoring calls between all CRAs assigned to
the project to discuss study issues and share information. This forum provides
an opportunity for the Lead CRA to coordinate monitoring efforts for maximum
efficiency across all regions/offices and to communicate important study updates
to the Project Team.
COMMUNICATIONS WITH SITES
Quintiles will contact the sites [________________] for patient enrollment
updates and to communicate any study administration information. All telephone
contacts with the sites will be documented. Quintiles' Clinical Monitoring Team
will be available by telephone to answer site questions throughout the course of
the study. After-hours coverage will be maintained by voicemail, and for urgent
matters, Quintiles will be accessible to sites through a 24-hour answering
service.
VI. MEDICAL MONITORING
MEDICAL SUPPORT
Quintiles will assign physician coverage to provide medical support for the
clinical monitors and Drug Safety Unit (as described in detail below). The
Project Medical Officer (PMO) will have a designated medical back-up and
Quintiles' medical staff will provide after hours on-call support for
Investigators to discuss project-related issues and questions.
[_______________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
_________]
-16-
The information below marked by * and [ ] has been omitted pursuant to a request
for confidential treatment. The omitted portion has been separately filed with
the Commission.
SERIOUS ADVERSE EVENT (SAE) AND EXPEDITABLE AE REPORTING
[_______________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
_________]
[_______________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
_________]
EXPEDITABLE AE WORKFLOW
All expeditable AEs will be reported by investigative sites directly to
Quintiles' Drug Safety Unit using a dedicated toll-free AE hotline. Interneuron
will receive a standard report of information for each patient event (CRFs,
source documents, sponsor-specified safety reporting forms, and narratives).
Quintiles will provide to Interneuron a standard report that includes all
information available on each SAE case, typically within 24 hours of first
notification from the site.
FDA REPORTING
Any report classified by Quintiles as a possible FDA safety report will have a
report drafted that includes a description of the case and a discussion of the
case in light of similar reports (the latter information may be provided by
Interneuron). The case will be reviewed by Quintiles' Drug Safety senior
management Quintiles will confirm with Interneuron all IND safety reports to be
reported to the FDA. Quintiles will submit the safety report to Interneuron.
DRUG SAFETY DATABASES
Quintiles will create a real-time safety database that originates from the
expeditable safety reports. Quintiles does not expect that end-of-study
reconciliation of safety and clinical data will be necessary. In the event that
safety and clinical data require reconciliation, Quintiles will agree with
Interneuron on a set of key fields that will be reconciled on a periodic basis.
-17-
The information below marked by * and [ ] has been omitted pursuant to a request
for confidential treatment. The omitted portion has been separately filed with
the Commission.
DRUG SAFETY PROCEDURES
Quintiles, in collaboration with Interneuron, will define the procedures for the
collection, evaluation, and reporting of SAEs. These procedures will include
definitions of expeditable events, delineation of SAE workflow from site to
Quintiles to Interneuron, and audits of the SAE system to guarantee proper
collection and reporting. Quintiles will be responsible for follow-up of SAE
reports and final preparation of the patient adverse event narratives. Based on
the specifications provided by Interneuron, Quintiles anticipates approximately
[_________________________________________________________]
VII. CLINICAL DATA MANAGEMENT
[_______________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
__________________________________]
DATA FLOW
Data will be collected from the study site by a citicoline project study
monitor. Only completed CRFs will be collected.
Once data are received at Quintiles, they will immediately go through a
preliminary auditing procedure and Clinical Document Administration, which
includes date stamping, log in, and transmittal verification.
Documents will be tracked on a patient-by-patient, page-by-page basis. Tracking
reports will be generated on a regular basis to identify and account for missing
pages, missing visits, and overall data accumulation. In addition, verification
of transmittals will occur on a regular basis with appropriate feedback to the
citicoline study team.
DATA REVIEW PROCEDURES
Clinical data will be reviewed using specifications developed by Quintiles and
approved by Interneuron. A combination of three types of data review procedures
will be employed:
[_______________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
_________________________________]
-18-
The information below marked by * and [ ] has been omitted pursuant to a request
for confidential treatment. The omitted portion has been separately filed with
the Commission.
PROGRAMMING
Quintiles will develop and test a: data entry system including data entry
screens and programmed error checks in SAS/FSP.
DATA ENTRY/OPTICAL XXXX RECOGNITION
[_______________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
_______________________________________________________________________________]
[_______________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
_______________________________________________]
[_______________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
__________________________________]
[_______________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
__________________________________]
DATA CLARIFICATION WITH THE INVESTIGATIVE SITE
Discrepancies or problems identified either during data review or entry will be
referred by the Quintiles data processing staff to the citicoline project study
monitor for resolution. All clarifications will be documented in writing using
Quintiles' standard operating procedures. This system represents a "controlled"
system in the sense that a full audit trail is produced and maintained for
problems encountered during both the
-19-
The information below marked by * and [ ] has been omitted pursuant to a request
for confidential treatment. The omitted portion has been separately filed with
the Commission.
data monitoring and data entry processes and for the resolution of each problem
referred to the study monitor.
QUALITY ASSURANCE
The quality of the final database is assured through a series of quality control
steps applied during processing, including double entry (or double scanning) of
all data. In addition, a final quality control audit will be performed prior to
locking the database. This is accomplished through proofreading a statistically
determined sample of data forms based on a number of criteria. The audit will
involve a 100% check of critical . variables identified by Interneuron and
Quintiles, and a 10% check of all other variables. The audit is conducted by
comparing the data forms against the final database. All audit results will be
documented for review by Interneuron.
ADVERSE EVENT/CONCOMITANT MEDICATION CODING
Quintiles will perform encoding of adverse events using
[____________________________] provided by Interneuron. Similarly, Quintiles
will provide encoding of prior or concurrent medications using
[______________________________]
DATABASE AUDIT
[_______________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
_________________________________]
VIII. BIOSTATISTICAL ANALYSIS
[_______________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
_________________________________]
STATISTICAL ANALYSIS PLAN
-20-
The information below marked by * and [ ] has been omitted pursuant to a request
for confidential treatment. The omitted portion has been separately filed with
the Commission.
Quintiles' Biostatisticians will prepare a data analysis plan that outlines the
trial's key efficacy and safety objectives, specifies the way in which variables
will be analyzed, and describes ancillary information that will be summarized in
the final report.
The analysis plan will summarize both descriptive and analytic statistics so
that the resulting reports will include a balance of understandable summaries of
the data, as well as the appropriate statistical tests.: All analysis plans will
be reviewed by a Senior Biostatistician at Quintiles before they are sent to
Interneuron. After approval of these plans by Interneuron, Quintiles'
Biostatisticians will finalize the analysis plan that will become the blueprint
for programming, analysis, and report-writing.
The Statistical Programmers assigned to this project will develop SAS programs,
and run the table output and patient listings required under the analysis plans.
Clinical Research Scientists will work with the Biostatistician during the
review of the analysis plans to prepare for clinical summary integration into
the final study reports Biostatistical Assistants will perform data quality
control activities reviewing all data listings, tables, and reports according to
Quintiles' RDQC standard SOPs.
[_______________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
________________________________________________________________]
FINAL ANALYSIS
Quintiles will prepare [______________] drafts of the final analysis for review
and comment by Interneuron. Once final comments from Interneuron are received,
the final analysis can be generated. The final analysis will be generated based
on the final, approved statistical analysis plan.
FINAL STUDY REPORT
Quintiles will prepare the integrated statistical clinical report section. The
draft final study report will be reviewed by internal Quintiles senior staff who
have the appropriate statistical and medical expertise.
Once internally reviewed, Quintiles will provide Interneuron with the draft
final study report for review and comment. The time for Interneuron's review is
estimated to be
-21-
The information below marked by * and [ ] has been omitted pursuant to a request
for confidential treatment. The omitted portion has been separately filed with
the Commission.
two (2) weeks. The report will be revised as needed based on comments from
Interneuron's review. Quintiles will deliver the final study report after
incorporating Interneuron's comments on the draft. Electronic copies of the
final study reports will be included. For scheduling purposes for this proposal,
Quintiles estimates that the final study report will be submitted for review two
months after database lock.
-22-
The information below marked by * and [ ] has been omitted pursuant to a request
for confidential treatment. The omitted portion has been separately filed with
the Commission.
EXHIBIT NO. 1
QUINTILES LABORATORIES LIMITED
PROPOSAL FOR CENTRAL LABORATORY SERVICES
INTERNEURON PHARMACEUTICALS, INC.
PROTOCOL [_________] *
JULY 3, 1996
REVISED FROM APRIL 11, 1996
1
The information below marked by * and [ ] has been omitted pursuant to a request
for confidential treatment. The omitted portion has been separately filed with
the Commission.
OVERVIEW
Quintiles Laboratories Limited (QLAB) is a global centralized clinical trial
laboratory serving exclusively clients in the pharmaceutical and biotechnology
marketplace. Operating as an independent business unit in the Quintiles family,
QLAB conducts clinical trials in conjunction with Quintiles' Contract Research
Organization (CRO) divisions, with other CROs or directly with sponsor
pharmaceutical companies. Quintiles Laboratories also provides centralized
clinical trial activities for European based studies from our facility in
Edinburgh, Scotland. Using identical instrumentation, reference ranges and
clinical trial software, QLAB North America and QLAB Europe provide the most
comprehensive North American and European central laboratory capabilities
currently in existence.
APPROACH TO AND EXPERIENCE IN NORTH AMERICAN AND EUROPEAN PROJECTS
Centralized clinical laboratory services for the U.S. and Canadian sites are
provided by Quintiles Laboratories in Atlanta, GA. European investigator sites
are serviced by Quintiles Laboratories Europe out of Edinburgh, Scotland.
[_______________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
_________________________________]
2
The information below marked by * and [ ] has been omitted pursuant to a request
for confidential treatment. The omitted portion has been separately filed with
the Commission.
[_______________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
_________________________________]
FACILITIES
[_______________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
_________________________________]
Both the North American and the European facilities are continuously monitored
by security specialists to ensure maximal protection against unauthorized access
to proprietary clinical trial materials and to provide early detection in the
event that the temperature controlled environments should go out of range or an
equipment failure should occur.
LICENSURE AND PROFICIENCY
[_______________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
_________________________________]
3
The information below marked by * and [ ] has been omitted pursuant to a request
for confidential treatment. The omitted portion has been separately filed with
the Commission.
ANALYTICAL CAPABILITIES
Both QLAB North America and QLAB Europe are comprehensive, full-service
facilities which provide analytical testing and data management services to meet
the needs of Phase I through Phase IV clinical trial programs. Both laboratories
use state of the art, automated instrumentation, chosen to optimize accuracy and
precision. High volume instrumentation are equipped with bar code readers and
are interfaced with the respective North American and European mainframe
databases.
[_______________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
_________________________________]
ANALYTICAL CHEMISTRY AND METHODS DEVELOPMENT
[_______________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
_________________________________]
PROTOCOL PLANNING AND MANAGEMENT
QLAB's staff of experienced clinical trial professionals will work with
Interneuron's project team or their designate in the planning of the laboratory
aspects of the
4
The information below marked by * and [ ] has been omitted pursuant to a
request for confidential treatment. The omitted portion has been separately
filed with the Commission.
protocols. A customized database which defines protocol specific parameters will
be developed at the beginning of the process. This approach will ensure that all
aspects of the program will be implemented smoothly and that the worldwide
laboratory database fully reflects the requirements of the protocol.
At study initiation, the design and development of customized visit and site
specific laboratory collection materials, laboratory reporting forms and
standard operating procedures will occur. Once Interneuron's approval of the
laboratory-related study materials has been received, a full presentation of the
laboratory aspects of the program can occur at the Investigator Meetings.
Throughout the program, professional, efficient and timely response to both
investigator's sites and Interneuron will be a priority.
Routine reporting of study status is available to assist Interneuron in the
study management of enrollment levels on a site by site basis. Additionally,
Interneuron may request patient abnormality or alert flag summaries to assist in
the identification of potentially early trends in the clinical trail.
Throughout the program, or at study conclusion, a complete audited database will
be electronically transmitted to Interneuron in a format and media that is
specified at the inception of the trial. This approach ensures that data is
ready for analysis as it is available from the central laboratories.
5
The information below marked by * and [ ] has been omitted pursuant to a
request for confidential treatment. The omitted portion has been separately
filed with the Commission.
[_______________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
_________________________________]
SPECIMEN COLLECTION AND RECEIPT
The designated QLAB facility will work with Interneuron to provide visit-
specific collection materials and overnight express courier shipping which will
meet the needs of Interneuron's protocol in the most cost-effective manner.
Because QLAB recognizes that the results for all specimens are important for the
successful and timely completion of your study, QLAB will provide:
[_______________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
_________________________________]
SAMPLE MANAGEMENT AND ARCHIVAL SERVICES
QLAB can provide sophisticated specimen management services which allows
deferred shipment of Interneuron's specimens to the central laboratory.
Collection of samples intended for periodic shipment to QLAB by the
investigators throughout Europe and North America are facilitated by use of pre-
addressed foam mailers.
6
The information below marked by * and [ ] has been omitted pursuant to a request
for confidential treatment. The omitted portion has been separately filed with
the Commission.
Additionally, specimens are held at both facilities for seven days to allow for
repeat testing when needed.
LABORATORY REPORTING
Laboratory Reports can be designed as a Case Report Form page and thereby allow
the investigator to indicate the level of clinical significance, etiology coding
and medical comments if desired. To assist the investigator in patient
management, critical test results on the laboratory report can be flagged by
protocol-specific telephone and panic alerts as designated by Interneuron. Delta
flagging can also be used on the laboratory report to alert the investigator of
early changes in a particular result relative to a patient's baseline result.
Exclusion flagging is provided so assist the investigator in the enrollment
phase of the trial, or to identify prospective patients for study withdrawal.
[_______________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
_________________________________]
QLAB laboratory information system (QLIMS) provides the following laboratory
reporting features to support your clinical trial:
7
The information below marked by * and [ ] has been omitted pursuant to a
request for confidential treatment. The omitted portion has been separately
filed with the Commission.
[_______________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
_________________________________]
[_______________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
_________________________________]
STUDY DESIGN AND ANALYTICAL SERVICES
[_______________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
_________________________________________________________________]
I. ROUTINE SAFETY MEASURES
8
The information below marked by * and [ ] has been omitted pursuant to a request
for confidential treatment. The omitted portion has been separately filed with
the Commission.
[__________________________________________________________________________
___________________________________________________________________________
___________________________________________________________________________
________________________________________________]
[__________________________________________________________________________
___________________________________________________________________________
___________________________________________________________________________
___________________________________________________________________________
________________________________________________]
[__________________________________________________________________________
___________________________________________________________________________
___________________________________________________________________________
________________________________________________]
[__________________________________________________________________________
___________________________________________________________________________
___________________________________________________________________________
9
The information below marked by * and [ ] has been omitted pursuant to a request
for confidential treatment. The omitted portion has been separately filed with
the Commission.
___________________________________________________________________________
__________________]
[__________________________________________________________________________
___________________________________________________________________________
___________________________________________________________________________
________________________________________________]
[__________________________________________________________________________
___________________________________________________________________________
___________________________________________________________________________
________________________________________________]
[__________________________________________________________________________
__________________]
[__________________________________________________________________________
___________________________________________________________________________
___________________________________________________________________________
________________________________________________]
10
The information below marked by * and [ ] has been omitted pursuant to a
request for confidential treatment. The omitted portion has been separately
filed with the Commission.
ANALYTICAL STANDARDS AND CERTIFICATION
[_______________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
_________________________________]
ANALYTICAL METHODOLOGY COMPARABILITY
[____________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
____________________________________________]
SPECIMEN STABILITY
[____________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
____________________________________________]
TEST PRIORITY IN THE EVENT OF INSUFFICIENT SPECIMENS
[____________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
____________________________________________]
TEST REPORTING UNITS
[____________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
____________________________________________]
11
The information below marked by * and [ ] has been omitted pursuant to a request
for confidential treatment. The omitted portion has been separately filed with
the Commission.
LABORATORY EVENTS SCHEDULE
INTERNEURON PHARMACEUTICALS, INC.
PHASE III, ISCHEMIC STROKE STUDY
PROTOCOL [_________]
SITES: [_________]
ENROLLMENT PERIOD: [_________]
TREATMENT PERIOD: [_________]
FOLLOW UP PERIOD: [_________]
START DATE: [_________]
-------------------------------------------------------------------------------------------
TREATMENT PHASE/
WEEKS [1-6]
BASELINE/ -------------------- EARLY UNSCHED/
ASSESSMENTS PERFORMED DAY 0 [HOSPITAL TERM RETEST
DISCHARGE] WEEK[6]
-------------------------------------------------------------------------------------------
-------------------------------------------------------------------------------------------
No. of Patients [___] [___] [___] [_________] [________]
-------------------------------------------------------------------------------------------
Chemistry w/18 Constituents [_] [_] [_] [_] [_]
-------------------------------------------------------------------------------------------
Lipid Profile [_] [_] [_] [_] [_]
-------------------------------------------------------------------------------------------
Hematology w/Differential & [_] [_] [_] [_] [_]
Platelet Count
-------------------------------------------------------------------------------------------
Coagulation Profile [_] [_] [_] [_] [_]
-------------------------------------------------------------------------------------------
Urinalysis w/Microscopic [_] [_] [_] [_] [_]
-------------------------------------------------------------------------------------------
Serum Pregnancy [_] [_] [_] [_] [_]
-------------------------------------------------------------------------------------------
KEY:
- - SCHEDULED TEST
- - UNSCHEDULED TEST
- - REQUIRED FOR FEMALE PATIENTS OF CHILDBEARING POTENTIAL ONLY. OPTIONAL
FOR BUDGETING PURPOSES.
12
The information below marked by * and [ ] has been omitted pursuant to a request
for confidential treatment. The omitted portion has been separately filed with
the Commission.
PROVISIONAL SERVICES BUDGET
INTERNEURON PHARMACEUTICALS, INC.
PHASE III, ISCHEMIC STROKE STUDY
PROTOCOL [____________]
NO. OF PATIENT
SCHEDULED VISITS VISITS FEE EXTENDED FEE
------------------------------------------------------------------------------------------
DATA BASE CONSTRUCTION & MAINTENANCE [_] [________] [____________]
------------------------------------------------------------------------------------------
BASELINE/DAY 0 VISIT [________________] VISIT & [_____] [______] [__________]
WEEK [_] VISIT
------------------------------------------------------------------------------------------
PROVISIONAL SERVICES BUDGET [___________]
------------------------------------------------------------------------------------------
UNSCHEDULED & ANCILLARY
SERVICES DESCRIPTION FEE FOR SERVICE
------------------------------------------------------------------------------------------
UNSCHEDULED VISIT FEE [___________________________________] [_________]
------------------------------------------------------------------------------------------
EARLY TERM VISIT FEE [___________________________________] [_________]
------------------------------------------------------------------------------------------
OPTIONAL TEST FEE [___________________________________] [_________]
------------------------------------------------------------------------------------------
ELECTRONIC DATA TRANSFER [___________________________________] [_________]
(MONTHLY)
------------------------------------------------------------------------------------------
WEEKLY STATUS REPORT [___________________________________] [_________]
------------------------------------------------------------------------------------------
13
The information below marked by * and [ ] has been omitted pursuant to a request
for confidential treatment. The omitted portion has been separately filed with
the Commission.
LABORATORY REQUIREMENTS
INTERNEURON PHARMACEUTICALS, INC.
PHASE III, ISCHEMIC STROKE STUDY
PROTOCOL [__________]
CHEMISTRY [_________]
[_________]
[_________] URINALYSIS
[_________] [_________]
[_________] [_________]
[_________] [_________]
[_________] [_________]
[_________] [_________]
[_________] [_________]
[_________] [_________]
[_________] [_________]
[_________]
[_________] ENDOCRINOLOGY
[_________] [_________]
[_________]
[_________] [_________]
[_________]
[_________]
[_________]
LIPID PROFILE
[_________]
[_________]
[_________]
[_________]
HEMATOLOGY
[_________]
[_________]
[_________]
[_________]
[_________]
[_________]
[_________]
[_________]
COAGULATION PROFILE *
[_________]
[_________]
14
The information below marked by * and [ ] has been omitted pursuant to a request
for confidential treatment. The omitted portion has been separately filed with
the Commission.
ATTACHMENT NO.2
PAYMENT SCHEDULE
PROTOCOL NO. [________] *
PROJECT BUDGET
ACTIVITY BUDGET
Interneuron/Quintiles Study Start-up Meeting-May 24, 1996
[ ] Quintiles staff to attend [$ ]
Project Management and Support [ ]
Study Doc. Development/Project Initiation/Investigator Contracts [ ]
Pre-study Site Evaluation Visits [ ]
Study Coordinator Meeting Planning/Attendance/Participation [ ] [ ]
National Stroke Assn. Training Meeting [ ]
Clinical Trial Monitoring [ ]
Clinical Trial In-House/Site Contact/CRA Coordination/Support [ ]
Quality Assurance Audits [ ] [ ]
Medical Support: PMO Services, AE Processing and Reporting [ ]
Study Drug Management [ ]
Data Management (includes estimated OMR CRF design/development) [ ]
Biostatistical Analysis [ ]
Final Biostatistical Report and Final Integrated Clinical Study Report [ ]
Quintiles Laboratories Ltd. [ ]
TOTAL QUINTILES' FEES [$ ]
May 24, 1996 Meeting Travel [ ]
Estimated Monitoring Travel [ ]
Estimated QA Audit Travel [ ]
Estimated Study Coordinator Meeting [ ] [ ]
Nat'l Stroke Assn. Training Meeting Travel [ ]
Miscellaneous Costs: [ ]
Shipping costs (non-drug), telephone/fax, postage
copying/printing, supplies [ ]
TOTAL PASS-THROUGH COSTS [$ ]
The information below marked by * and [ ] has been omitted pursuant to a request
for confidential treatment. The omitted portion has been separately filed with
the Commission.
MONITORING VISIT UNIT COSTS
MONITORING ESTIMATED
ACTIVITY TIME TRAVEL COSTS TOTAL
-----------------------------------------------------------------------
Pre-Study Site Evaluation Visit [ ] [ ] [ ]
-----------------------------------------------------------------------
Site Initiation Visit [ ] [ ] [ ]
-----------------------------------------------------------------------
Interim Monitoring Visit [ ] [ ] [ ]
-----------------------------------------------------------------------
Site Closeout Visit [ ] [ ] [ ]
-----------------------------------------------------------------------
[_________________________________________________________________________]
-2-
The information below marked by * and [ ] has been omitted pursuant to a request
for confidential treatment. The omitted portion has been separately filed with
the Commission.
BUDGET NOTE
GENERAL
[__________________________________________________________________________
___________________________________________________________________________
__________________________________________________________________________]
[_______________________________________________________________________________
________________________________________________________________________________
_______________________________________________________________________________]
PROJECT INITIATION
[_______________________________________________________________________________
________________________________________________________________________________
______________________________________________________]
[_______________________________________________________________________________
________________________________________________________________________________
______________________________________________________]
[_______________________________________________________________________________
________________________________________________________________________________
______________________________________________________]
[_______________________________________________________________________________
________________________________________________________________________________
______________________________________________________]
[_______________________________________________________________________________
________________________________________________________________________________
______________________________________________________]
[_______________________________________________________________________________
________________________________________________________________________________
______________________________________________________]
[_______________________________________________________________________________
________________________________________________________________________________
______________________________________________________]
-3-
The information below marked by * and [ ] has been omitted pursuant to a request
for confidential treatment. The omitted portion has been separately filed with
the Commission.
[_______________________________________________________________________________
________________________________________________________________________________
______________________________________________________]
CLINICAL MONITORING AND PROJECT MANAGEMENT
[_______________________________________________________________________________
________________________________________________________________________________
______________________________________________________]
[_______________________________________________________________________________
________________________________________________________________________________
______________________________________________________]
[_______________________________________________________________________________
________________________________________________________________________________
______________________________________________________]
[_______________________________________________________________________________
________________________________________________________________________________
______________________________________________________]
[_______________________________________________________________________________
________________________________________________________________________________
______________________________________________________]
DATA MANAGEMENT
[_______________________________________________________________________________
________________________________________________________________________________
______________________________________________________]
[_______________________________________________________________________________
________________________________________________________________________________
______________________________________________________]
[_______________________________________________________________________________
________________________________________________________________________________
______________________________________________________]
BIOSTATISTICAL ANALYSIS
-4-
The information below marked by * and [ ] has been omitted pursuant to a request
for confidential treatment. The omitted portion has been separately filed with
the Commission.
[_______________________________________________________________________________
________________________________________________________________________________
______________________________________________________]
[_______________________________________________________________________________
________________________________________________________________________________
______________________________________________________]
[_______________________________________________________________________________
________________________________________________________________________________
______________________________________________________]
-5-
The information below marked by * and [ ] has been omitted pursuant to a request
for confidential treatment. The omitted portion has been separately filed with
the Commission.
ATTACHMENT NO.3
PAYMENT SCHEDULE
PROTOCOL NO. [________] *
Interneuron Pharmaceutical, Inc. agrees to pay Quintiles for services rendered
upon receipt of invoice according to the payment schedule detailed below.
A. Quintiles Fees
---------------------------------------------------------------
DATE
PAYMENT --------------------------
NO. AMOUNT INVOICED DUE
-------- ------------ ----------- ------------
#1 [$ ______] [_________________]
#2 [$ ______] [ ______] [ ______]
#3 [$ ______] [ ______] [ ______]
#4 [$ ______] [ ______] [ ______]
#5 [$ ______] [ ______] [ ______]
#6 [$ ______] [ ______] [ ______]
#7 [$ ______] [ ______] [ ______]
#8 [$ ______] [ ______] [ ______]
#9 [$ ______] [ ______] [ ______]
#10 [$ ______*] [ ______] [ ______]
B. Pass-Through Costs
[______________________________________________________________________
________________________________________________________________________________
______________________________________________________]
[_______________________________________________________________________________
________________________________________________________________________________
______________________________________________________]
VARIABLE COST ITEMS
[_______________________________________________________________________________
________________________________________________________________________________
______________________________________________________]
