EXHIBIT 10.96
CLINICAL RESEARCH SERVICES AGREEMENT
This agreement ("Agreement") is made this 25th day of January, 1999,
by and between Xxxxxxxxxx Laboratories, Inc., with its principal
executive offices located at 0000 Xxxxxx Xxxx Xxxx, Xxxxxx, Xxxxx 00000
("Sponsor"or "Xxxxxxxxxx"), and PPD Pharmaco, Inc., a Texas corporation
with its principal executive offices located at 0000 00xx Xxxxxx
Xxxxxxxxx, Xxxxxxxxxx, Xxxxx Xxxxxxxx 00000 XXX ("PPD Pharmaco").
WHEREAS, Sponsor is engaged in the development, manufacture,
distribution, and sale of pharmaceutical products; and
WHEREAS, PPD Pharmaco is a contract research organization engaged in
the business of managing clinical research programs; and
WHEREAS, Sponsor wishes to retain the services of PPD Pharmaco to
perform clinical research services in connection with the clinical
research Study entitled "A Double-Blind, Randomized, Placebo-Controlled
Study Of The Safety And Efficacy Of Three Dose Regimens Of Oral Aliminase
In The Treatment Of Active Ulcerative Colitis" ("Study") to be conducted
pursuant to Sponsor's Study Protocol #9084 incorporated herein by
reference ("Protocol"); and
WHEREAS, PPD Pharmaco is willing to provide such services to Sponsor
in accordance with the terms and conditions of this Agreement;
NOW, THEREFORE, for good and valuable consideration contained
herein, the exchange, receipt and sufficiency of which are acknowledged,
the parties agree as follows:
1. Services.
1.1 - PPD Pharmaco shall perform services as set forth in the
Statement of Services and Description of Services attached as Exhibit A
and incorporated herein by reference ("Services"). PPD Pharmaco shall
provide said Services in compliance with the Protocol, this Agreement,
the written instructions of Sponsor, PPD Pharmaco's Standard Operating
Procedures ("SOPs"), and all applicable laws, rules, and regulations.
SOPs are subject to revision by PPD Pharmaco in which case PPD Pharmaco
shall notify Sponsor of revision. If any such SOP revision can be
reasonably expected to affect the budget or timelines for the Study, PPD
Pharmaco shall submit to Sponsor revised cost estimates or timelines for
the relevant Services which will become a part of this Agreement upon
written approval by Sponsor. The current SOPs for conducting and
monitoring clinical trials are available for review upon request by
Sponsor.
Upon mutual agreement in writing, the parties may conduct the Study
under Sponsor's SOPs. In such case, Sponsor shall provide prompt and
reasonable training to any PPD Pharmaco personnel subject to such SOPs at
Sponsor's expense.
1.2 - To the extent that any of Sponsors obligations under 21 C.F.R.
312.52 consist of Services that are to be performed by PPD Pharmaco under
this Agreement, such obligations are hereby transferred by Sponsor to PPD
Pharmaco for purposes of 21 C.F.R. Section 312.52.
1.3 - In the event that PPD Pharmaco is requested or required to
perform services beyond those which are specifically set forth in this
Agreement, any such additional services and a compensation schedule
therefor must be mutually agreed upon by the parties in writing prior to
the provision of said services. Said mutually agreed upon writing shall
be an addendum to this Agreement and the services set forth therein shall
be deemed to be Services as the term is used in this Agreement.
1.4 - Sponsor may audit PPD Pharmaco and/or one or more
investigational sites participating in the Study, provided Sponsor gives
prior written notice of any such audit to PPD Pharmaco and any
investigational site to be audited. PPD Pharmaco shall cooperate fully
in any such audit provided said audits are performed during PPD Pharmaco
regular working hours.
2. Compensation and Payment.
2.1 - For its performance of Services under this Agreement, PPD
Pharmaco shall receive compensation as set forth in the Payment Schedule
attached as Exhibit B and incorporated herein by reference.
2.2 - PPD Pharmaco shall submit to Sponsor an invoice describing the
indirect pass through costs and expenses incurred during a particular
month on a monthly basis and Sponsor shall pay said invoices within
thirty (30) days of receipt. Investigator initiation costs and central
lab costs will be invoiced upfront and shall be due upon sponsor s
receipt of invoice.
2.3 - In the event this Agreement is terminated pursuant to Section
3 below, PPD Pharmaco shall be compensated for all fees and costs due
pursuant to the Payment Schedule as of the effective date of termination.
Additionally, Sponsor shall reimburse PPD Pharmaco for any and all
amounts that it pays to third parties for uncancellable obligations that
PPD Pharmaco made with respect to the Study and with the approval of
Sponsor; provided however, that the preceding portion of this sentence
shall not be applicable if this Agreement is terminated (i) by PPD
Pharmaco without cause or (ii) by either party because PPD Pharmaco is
the subject of any of the events specified in Section 3.3 or (iii) by
Sponsor with cause. Any funds held by PPD Pharmaco which shall be shown
by Sponsor to be unearned at the date of termination shall be returned to
Sponsor within forty-five (45) days of termination of this Agreement.
2.4 - In the event the Study is terminated early or reduced in
scope, in addition to any and all other compensation and reimbursement
due under this Agreement, Sponsor shall pay to PPD Pharmaco an amount, as
determined by PPD Pharmaco in good faith, to represent costs and expenses
incurred as a result of said early termination or reduction in scope,
including by way of example but not limited to, unforeseen down time and
reassignment of PPD Pharmaco dedicated Study personnel ("Termination
Expenses"). Said Termination Expenses shall not exceed 15% of the total
fees (excluding pass through expenses and any fee payments already made
to PPD Pharmaco) PPD Pharmaco would have received pursuant to this
Agreement had the Study continued full scope until completion. The
foregoing provisions of this Section 2.4 shall not be applicable if the
Study is terminated early because of a termination of this Agreement (i)
by PPD Pharmaco without cause or (ii) by either party because PPD
Pharmaco is the subject of any of the events specified in Section 3.3 or
(iii)by Sponsor with cause, or because the Food & Drug Administration
("FDA") withdraws its authorization and approval to perform the Study, or
because any adverse reaction or side effect resulting form the use of the
Study drug is of such magnitude or incidence as to warrant termination of
the Study in the sole opinion of the Sponsor.
2.5 - Payments to PPD Pharmaco shall be made to:
PPD Pharmaco, Inc.
X.X. Xxx 00000
Xxxxxxxxx, Xxxxx Xxxxxxxx 00000-0000
Tax ID# 00-0000000
2.6 - Taxes (and any penalties thereon) imposed on any payment made
by Sponsor to PPD Pharmaco shall be the responsibility of PPD Pharmaco.
3. Term and Termination.
3.1 - The term of this Agreement shall commence as of the date
hereof and end upon completion of the Services unless earlier terminated
in accordance with this Section 3.
3.2 - This Agreement may be terminated with or without cause by
either party upon thirty (30) days prior written notice.
3.3 - This Agreement may be terminated by either party upon fifteen
(15) days prior written notice if the other party becomes insolvent, is
dissolved or liquidated, makes a general assignment for the benefit of
its creditors, files or has filed against it (and does not obtain a
dismissal within ninety (90) days) a petition in bankruptcy, or has a
receiver appointed for it or a substantial part of its assets.
3.4 - In the event of a material breach of this Agreement by either
party, the other party may terminate this Agreement, either immediately
or as of a future date, by giving the breaching party written notice of
termination, which notice shall state the effective date of termination
of this Agreement. Any such termination shall constitute a termination
with cause.
3.5 - Upon termination of this Agreement, PPD Pharmaco shall
cooperate with Sponsor to provide for an orderly wind-down of the
Services provided by PPD Pharmaco hereunder.
3.6 - The obligations of the parties contained in Sections 2.6, 3.5,
3.6, 5, 6, 7, 8, 11, 13, and 21 hereof shall survive termination of this
Agreement.
4. Personnel.
4.1 - The Services with respect to the Study shall be performed by
PPD Pharmaco under the direction of the person identified as the Project
Manager or such other person acceptable to Sponsor as PPD Pharmaco may
from time to time designate the Project Manager.
4.2 - PPD Pharmaco shall be obligated at all times to provide a
sufficient number of trained clinical research personnel to meet the
demands of the Study.
4.3 - PPD Pharmaco shall not subcontract or assign any Services
without the prior written consent of Sponsor, such consent not to be
unreasonably withheld.
4.4 - During the period in which the Study is being conducted,
neither party shall recruit, hire or employ any personnel of the other
who is material to the performance of the particular Study without the
prior written consent of the other party.
5. Confidentiality.
5.1 - PPD Pharmaco agrees to treat any confidential information
obtained from Sponsor or gathered or generated by PPD Pharmaco as a
direct and sole result of performing the Services under this Agreement,
including, without limitation, confidential commercial, scientific,
medical and technical information and data relating to Sponsor, a Study
drug or the Study (all such data and information together with any
information derived therefrom, exclusive of computer software or code
developed by PPD Pharmaco unless specifically included, to be referred to
herein as the "Information"), as the confidential and exclusive property
of Sponsor.
5.2 - PPD Pharmaco agrees that it will use any Information only to
provide the Services and for no other purpose without the prior written
consent of Sponsor. PPD Pharmaco agrees not to disclose any of the
Information to any third party without first obtaining the written
consent of Sponsor. PPD Pharmaco further agrees to take all reasonable
steps to ensure that the Information shall not be used by its directors,
officers, employees, agents, representatives and advisors, except on like
terms of confidentiality as aforesaid, and that it shall be kept fully
private and confidential by them.
The above provisions of confidentiality shall not apply to that part of
the Information which PPD Pharmaco is able to demonstrate by documentary
evidence:
a) was fully in PPD Pharmaco's possession prior to receipt from
Sponsor; or
b) was in the public domain at the time of receipt from Sponsor; or
becomes part of the public domain through no fault of PPD Pharmaco,
its directors, officers, employees, agents, representatives or
advisors; or
c) is lawfully received by PPD Pharmaco from some third party
having a right of further disclosure; or
d) is developed by PPD Pharmaco independent of the Information and
the Study; or
e) is required by law to be disclosed.
5.3 - PPD Pharmaco agrees that upon termination of this Agreement
or, at Sponsor's request, it shall return to Sponsor all Information
provided by Sponsor in documentary form, as well as all Information
gathered or generated by PPD Pharmaco in connection with the Study, and
return or destroy any copies thereof made by or for PPD Pharmaco.
Notwithstanding the foregoing, PPD Pharmaco may retain copies of any such
Information as is reasonably necessary for regulatory or insurance
purposes or as PPD Pharmaco deems necessary to demonstrate the
satisfaction of its obligations hereunder, all subject to the ongoing
obligation to maintain the confidentiality of such Information.
5.4 - PPD Pharmaco acknowledges that disclosure or distribution
of the Information or use of the Information contrary to the terms of
this Agreement may cause irreparable harm for which damages at law may
not be an adequate remedy, and agrees that the provisions of this
Agreement prohibiting disclosure or distribution of the Information or
use contrary to the provisions hereof may be specifically enforced by a
court of competent jurisdiction in addition to any and all other remedies
available at law or in equity.
6. Intellectual Property.
6.1 - PPD Pharmaco hereby assigns to Sponsor all rights PPD Pharmaco
or its directors, officers, employees, agents or representatives may have
in any invention, technology, know-how or other intellectual property
directly and solely resulting from PPD Pharmaco's provision of the
Services hereunder and agrees to assist Sponsor, at Sponsor's expense, in
obtaining or extending protection therefor, provided, however, that such
assignment shall not pertain to computer software or code unless
specifically agreed upon herein. PPD Pharmaco represents that it has and
will continue to have agreements with its directors, officers, employees,
agents and representatives to effectuate the terms of this Section and
shall enforce such agreements to provide Sponsor with the benefit of this
Section.
6.2 - Neither anything contained herein nor the delivery of any
Information to PPD Pharmaco shall be deemed to grant PPD Pharmaco any
right or licenses under any patents or patent applications or to any
know-how, technology or inventions of Sponsor.
6.3 - PPD Pharmaco agrees that Sponsor will own and have
unrestricted free right to use for all purposes the material, data and
information generated or created directly and solely as part of the
Services, provided, however, that such unrestricted free right to use
shall not pertain to computer software or code unless specifically agreed
upon herein. PPD Pharmaco represents and warrants that it is entitled to
deliver the material, data and information to be delivered as part of the
Services hereunder for Sponsor's free use.
7. Publication.
7.1 - PPD Pharmaco may not publish any articles or make any
presentations relating to the Services or referring to data, information
or materials generated as part of the Services, in whole or in part,
without the prior written consent of Sponsor. PPD Pharmaco shall not
disclose publicly or utilize in any advertising or promotional materials
the existence of this Agreement or PPD Pharmaco's association with
Sponsor or use Sponsor's name or the name of any of its divisions,
products or investigations except with Sponsor's prior written consent.
7.2 - Sponsor may use, refer to and disseminate reprints of
scientific, medical and other published articles that disclose the name
of PPD Pharmaco consistent with U.S. copyright laws, provided that such
use does not constitute an endorsement of any commercial product or
service by PPD Pharmaco.
8. Indemnification.
8.1 - Sponsor shall indemnify PPD Pharmaco, its directors, officers,
employees, and agents for any and all damages, costs, expenses and other
liabilities, including reasonable attorney's fees and court costs,
incurred in connection with any third-party claim, action or proceeding
arising from this Agreement or PPD Pharmaco's connection to the Study,
provided however, that Sponsor shall have no obligation hereunder with
respect to any claim, action or proceeding based on or arising from the
negligence or intentional misconduct on the part of PPD Pharmaco or any
of its directors, officers, employees, agents or representatives or
breach by PPD Pharmaco of any of its obligations under this Agreement or
any agreement between PPD Pharmaco and any third party.
8.2 - PPD Pharmaco shall indemnify Sponsor, its directors, officers
and employees for any and all damages, costs, expenses and other
liabilities, including reasonable attorney's fees and court costs,
incurred in connection with any third-party claim, action or proceeding
based or arising from the negligence or intentional misconduct of PPD
Pharmaco or any of its directors, officers, employees, agents or
representatives or breach of PPD Pharmaco of any of its obligations under
this Agreement.
8.3 - Any party liable to provide indemnification hereunder shall be
entitled, at its option, to control the defense and settlement of any
claim on which it is liable, provided that the indemnifying party shall
act reasonably and in good faith with respect to all matters relating to
the settlement or disposition of the claim as the disposition or
settlement relates to the party being indemnified. The indemnified party
shall reasonably cooperate in the investigation, defense and settlement
of any claim for which indemnification is sought hereunder and shall
provide prompt notice of any such claim or reasonably expected claim to
the indemnifying party.
9. Independent Contractor Relationship.
The parties hereto are independent contractors and nothing contained
in this Agreement shall be construed to place them in the relationship of
partners, principal and agent, employer/employee or joint venturer. Both
parties agree that they shall neither have the power or right to bind or
obligate the other, nor shall either hold itself out as having such
authority.
10. Conflicts.
PPD Pharmaco represents and warrants to Sponsor that PPD Pharmaco is
not a party to any agreement which would prevent it from fulfilling its
obligations under this Agreement. During the term of this Agreement, PPD
Pharmaco (i) will not enter into any agreement that would in any way
restrict its ability to provide Services under this Agreement and (ii)
will not enter into any other agreements to provide study services in
connection with ulcerative colitis that would adversely affect its
ability to meet the timelines established for Sponsor's Study.
11. Publicity.
Except as required by law, neither party shall use the name of the
other party nor of any employee of the other party in connection with any
publicity without the prior written approval of the other party.
12. Force Majeure / Delays.
12.1 - In the event either party shall be delayed or hindered in or
prevented from the performance of any act required hereunder by reasons
of strike, lockouts, labor troubles, restrictive government or judicial
orders, or decrees riots, insurrection, war, Acts of God, inclement
weather or other similar reason or a cause beyond such party's control,
then performance of such act shall be excused for the period of such
delay. Notice of the start and stop of any such force majeure shall be
provided to the other party.
12.2 - To the extent either party is delayed for reasons as set
forth above or for other reasons beyond the control of the affected
party, any timeline or milestone obligations of said party shall be
extended for a period of time equal to the number of days of the delay.
13. Record Storage.
13.1 - During the term of this Agreement, PPD Pharmaco shall
maintain all materials and all other data obtained or generated by PPD
Pharmaco in the course of providing the Services hereunder, including all
computerized records and files, in a secure area reasonably protected
from fire, theft and destruction. PPD Pharmaco shall cooperate with any
internal review or audit by Sponsor and make available to Sponsor for
examination and duplication, during normal business hours and at mutually
agreeable times, all documentation, data and information relating to the
Study.
13.2 - At the expiration or termination of this Agreement and upon
written instruction of Sponsor, all materials and all other data and
information obtained or generated by PPD Pharmaco in the course of
providing the Services hereunder shall, at Sponsor's option, be (i)
delivered to Sponsor at its Research and Development offices in Irving,
TX in such form as is then currently in the possession of PPD Pharmaco,
(ii) retained by PPD Pharmaco for Sponsor for a period of three years, or
(iii) disposed of, at the direction and written request of Sponsor,
unless such materials are otherwise required to be stored or maintained
by PPD Pharmaco as a matter of law or regulation. Sponsor shall have
sole responsibility for the costs of shipping of the materials referred
to herein. Sponsor shall retain and be responsible for the performance
of any carrier designated by Sponsor for the shipping of materials. In
no event shall PPD Pharmaco dispose of any materials or data or other
information obtained or generated by PPD Pharmaco in the course of
providing the Services hereunder without first giving Sponsor sixty (60)
days prior written notice of its intent to do so. Notwithstanding the
foregoing, PPD Pharmaco may retain copies of any of the materials
referred to herein as are deemed reasonably necessary, in PPD Pharmaco s
sole reasonable discretion, for regulatory or insurance purposes or to
demonstrate the performance of its obligations hereunder, subject to its
ongoing obligation to maintain the confidentiality of such materials.
14. Debarment.
14.1 - PPD Pharmaco hereby certifies that it has not been debarred,
and has not been convicted of a crime which could lead to debarment,
under the Generic Drug Enforcement Act of 1992, 21 United States Code
ss306(a) and (b). In the event that PPD Pharmaco or any of its officers,
directors, or employees under contract to perform Services under the
Study becomes debarred or receives notice of action or threat of action
with respect to its debarment, PPD Pharmaco shall notify Sponsor
immediately. If PPD Pharmaco is the subject of such debarment or
threatened debarment, Sponsor shall have the option of terminating this
Agreement with cause, either immediately or as of a future date selected
by Sponsor, by giving PPD Pharmaco written notice of termination, which
notice shall state the effective date of termination of this Agreement.
If one or more individuals are the subject of such debarment or
threatened debarment, PPD Pharmaco shall, if Sponsor so requests,
terminate the participation of such individual(s) in the Study.
14.2 - PPD Pharmaco hereby certifies that it has not utilized, and
will use its reasonable best efforts not to utilize, the services of any
individual or entity in the performance of services under this Agreement
that has been debarred or that has been convicted of a crime which could
lead to debarment under the Generic Drug Enforcement Act of 1992, 21
United States Code ss306(a) and (b). In the event that PPD Pharmaco
receives notice of the debarment or threatened debarment of any such
individual or entity, PPD Pharmaco shall notify Sponsor immediately and
shall, if Sponsor so requests, terminate the participation of such
individual or entity in the Study.
15. Notices.
Any notice required or permitted to be given hereunder by either
party hereunder shall be in writing and shall be deemed given on the date
received if delivered personally or by fax or five (5) days after the
date postmarked if sent by registered or certified U.S. mail, return
receipt requested, postage prepaid to the following applicable address:
If to PPD Pharmaco: PPD Pharmaco, Inc.
0000 00xx Xxxxxx Xxxxxxxxx
Xxxxxxxxxx, Xxxxx Xxxxxxxx 00000
Attention: CEO
Tel: (000) 000-0000
Fax: (000)000-0000
If to Sponsor: Xxxxxxxxxx Laboratories, Inc.
0000 Xxxxxx Xxxx Xxxx
Xxxxxx, Xxxxx 00000
Attention: Dr. Xxxx Xxxxx
Tel: (000) 000-0000
Fax: (000) 000-0000
16. Governing Law.
This Agreement and the rights and obligations of the parties
hereunder shall be governed by the laws of the State of Texas.
17. Severance.
If any one or more provisions of this Agreement shall be found to be
illegal or unenforceable in any respect, the validity, legality and
enforceability of the remaining provisions shall not in any way be
affected or impaired thereby, provided the surviving agreement materially
comports with the parties original intent.
18. Waiver.
Waiver or forbearance by either party or the failure by either party
to claim a breach of any provision of this Agreement or exercise any
right or remedy provided by this Agreement or applicable law, shall not
be deemed to constitute a waiver with respect to any subsequent breach of
any provision hereof.
19. Changes and Modification.
No changes or modifications of this Agreement shall be deemed
effective unless in writing and executed by the parties hereto.
20. Assignment.
This Agreement may not be assigned by either party without the prior
written consent of the other party, provided, however, either party may
assign this Agreement to a successor to such party's business interests.
21. Arbitration.
In the event that any dispute arises hereunder or with respect to
the Services to be provided as set forth herein, the parties agree to
submit such dispute to binding arbitration pursuant to the Commercial
Arbitration Rules of the American Arbitration Association in Austin,
Texas. The parties shall be entitled to conduct reasonable discovery, in
accordance with the Federal Rules of Civil Procedure, prior to the
arbitration hearing and the Federal Rules of Evidence The decision of
the arbitrators shall be final and binding and enforceable by any court
of competent jurisdiction.
22. Entire Agreement.
This Agreement represents the complete and entire understanding
between the parties regarding the subject matter hereof and supersedes
all prior negotiations, representations or agreements, either written or
oral, regarding this subject matter.
IN WITNESS THEREOF, this Agreement has been executed by the parties
hereto through their duly authorized officers as of the date set forth
above.
ACCEPTED:
PPD Pharmaco, Inc. Xxxxxxxxxx Laboratories, Inc.
By /s/ Xxxx X. Xxxxxxxxx, M.D. By: /s/ Xxxxxxx X. Xxxxxx, Ph.D.
Name: Xxxx X. Xxxxxxxxx, M.D. Name: Xxxxxxx X. Xxxxxx, Ph.D.
Title: Sr. VP Med Affairs/C.S.O. Title: President/CEO
Date: January 21, 1999 Date: January 25, 1999
EXHIBIT A
A Double-Blind, Randomized, Placebo-Controlled Study Of The
Safety And Efficacy Of Three Dose Regimens Of Oral
Aliminase[TM] In The Treatment Of Active Ulcerative Colitis
Protocol: 9084
Prepared For:
Dr. Xxxxxxx (Xxxx) Xxxxx
Xxxxxxxxxx Laboratories, Inc.
0000 X. Xxxxxxxx
Xxxxxx, XX 00000
October 29, 1998
1st Revision: November 6, 1998
2nd Revision: November 19, 1998
3rd Revision: December 9, 1998
4th Revision: January 4, 1999
5th Revision: January 19, 1999
Confidential
B&C# 8388
OVERVIEW
Ulcerative colitis (UC) is an inflammatory disease of the colon that
affects about 0.05 to 0.1% of the general population. Lifelong sporadic
flare-ups with fever, cramps, weight loss and persistent rectal bleeding
and diarrhea with severe inflammation of the colon characterize
ulcerative colitis. The cause of UC is unknown and although mild to
moderate disease usually can be managed with prednisone, mesalamine or
sulfasalazine; there is no cure.
Aliminase[TM] is an investigational compound under development by
Xxxxxxxxxx Laboratories, Inc. Aliminase[TM] is extracted from the gel of
the aloe barbadensis plant. When applied topically, acemannan has been
demonstrated to have an anti-inflammatory effect in an animal model. A
pharmacokinetic Study in dogs, demonstrated that orally administered
Aliminase[TM] coats the entire GI tract. In sufficient quantities,
Aliminase[TM] could coat the mucosa of the colon and produce a localized
anti-inflammatory effect. Subsequent studies in Dextran Sulphate-induced
colitis in a mouse model confirmed that Aliminase[TM] reduced colonic
damage in a dose-dependent manner that was at least as, if not more,
effective than Sulfasalazine or Cyclosporin.
An open-label clinical trial in which patients with active UC were
treated with either 800 mg or 1600 mg of oral acemannan/day demonstrated
statistically significant improvements in the disease activity index
(DAI) and signs and symptoms evaluations in patients treated for four (4)
weeks, no significant adverse events occurred during the trial. These
results were sufficient to encourage further clinical investigation in
the treatment of UC patients with Aliminase[TM] capsules.
A large scale multi-center controlled trial was performed in 311 patients
with active UC who were randomized to either placebo, 30 mg, 600 mg or
1200 mg of Aliminase[TM] capsules for 6 weeks. This Study, possibly due
to variable and inconsistent dissolution of capsules, failed to show any
significant differences between the groups in efficacy endpoints.
With this in mind, Xxxxxxxxxx Laboratories, Inc. has designed a clinical
trial entitled:
"A Double-Blind, Randomized, Placebo-Controlled Study Of The
Safety And Efficacy Of Three Dose Regimens Of Oral Aliminase[TM]
In The Treatment Of Active Ulcerative Colitis"
Xxxxxxxxxx and PPD Pharmaco agree that PPD Pharmaco shall manage and
monitor this clinical trial. Additionally, PPD Pharmaco shall be
responsible for handling the data management and biostatistics
portion of the Study. This Study is a 6-week, double blind,
randomized, placebo-controlled Study in which approximately 280
patients who are experiencing acutely active or relapsing UC will be
treated with either oral placebo or oral Aliminase[TM]. The trial
will be conducted in approximately 40 centers.
STUDY OBJECTIVES
The objectives of the Study are to assess the safety and
effectiveness of three dose regimens of Aliminase[TM] in the
treatment of active UC. Safety will be measured by laboratory tests
and documentation of adverse events. Efficacy will be measured by
the following parameters: Disease Activity Index (DAI) and quality
of life according to the Inflammatory Bowel Disease Questionnaire
(IBDQ). Sigmoidoscopic examinations will be performed at screening
and at week 6 or at withdrawal, at which time DAI scores will be
recorded. IBDQ will be assessed and scores recorded at screening and
at week 6 or at withdrawal.
Remainder of this page left blank
PROJECT ASSUMPTIONS
1. PPD Pharmaco will manage and monitor the Study according to GCPs
and PPD Pharmaco SOPs.
2. Xxxxxxxxxx will be responsible for the Study design and will
write the Protocol.
3. PPD Pharmaco will assist in the development of the case report
form (CRF).
4. PPD Pharmaco will print and distribute the CRF.
5. PPD Pharmaco will design a standard template informed consent.
6. PPD Pharmaco will provide drug logs for site use.
7. The final review and resolution of all changes to the informed
consent form will be the responsibility of PPD Pharmaco subject
to Xxxxxxxxxx approval.
8. PPD Pharmaco will prepare and set-up original investigator files
per Xxxxxxxxxx instructions. PPD Pharmaco will prepare and
set-up investigator file copies per PPD Pharmaco SOPs.
9. Randomization will begin no more than 2.5 months after the
Protocol and informed consent form are finalized.
10. There will be 40 investigative sites.
11. At least 80% of investigational sites will use a Central IRB.
12. The enrollment rate is anticipated to be .9 patients per site per
month.
13. Interim monitoring visits will occur at 6-week intervals,
intervals may be compressed or expanded due to enrollment at a
Study site.
14. Each patient's CRFs will be retrieved only as a completed set.
Patient data (CRFs) will not be retrieved as independent pages.
15. The total PPD Pharmaco time commitment is expected to be
approximately 16 months.
16. Xxxxxxxxxx will have final authority to approve investigators.
17. The delivery format of the database is assumed to be SAS
datasets, where PPD Pharmaco has specified the variable names.
18. SAS programs and interim datasets produced as part of the
analysis are not deliverable. These could be provided but would
need some additional effort for documentation.
19. It is assumed that there will be 1 test transfer and 1 final data
transfer. There will be no interim data transfers.
20. The Integrated Clinical Statistical Report (ICSR) price is based
on the following assumptions:
* The report will be written using a template or format agreed upon
by Xxxxxxxxxx Labs and PPD Pharmaco. Any changes in the format
after specifications have been reviewed and approved by
Xxxxxxxxxx may result in additional costs.
* The report will be written from tables and listings provided by
PPD Pharmaco
* The Sponsor will receive one draft for review and one final
version of the report
* The Sponsor will submit all review comments simultaneously
21. Central Laboratories price is based on the following assumptions:
* Clear View Pregnancy test kits will be sent to each site and
performed on 50% of subjects at Screening Visit
* Hematology panel includes an automated differential
* Federal Express cost will be directly passed on to the Sponsor
* Electronic transmission of management reports to Sponsor and
CRO: $25.00 per transmission
* Proposal does not include unscheduled/repeat visits, confirmation,
or additional testing ordered by the Investigator, and as approved
by the medical monitor
22. Biostatistical assumptions concerning productions of tables,
listings and graphs:
* A select initial subset of the summary tables, listings and
graphs (TLGs) not to exceed 25 will be finalized within 4 weeks
of database lock. The timing for these will be:
* Week 1: Print and final validation
* Week 2: QC review, correct and ship to Sponsor for review
* Week 3: Sponsor review
* Week 4: Revise, revalidate and ship final TLGs to Sponsor
and give to medical writing
* For the rest of the TLGs the following schedule will be
followed:
* Week 1: Print
* Week 2&3: Final validation and corrections
* Week 4: QC Review, correct and ship to Sponsor for review
* Week 5: Sponsor Review
* Week 6&7: Revise, revalidate and give remaining final TLGs
to medical writing
23. This Agreement does not include data entry of CRF pages for screen
failures.
PROJECT SPECIFICATIONS
Protocol Title: A Double-Blind, Randomized, Placebo-Controlled Study Of
The Safety And Efficacy Of Three Dose Regimens Of Oral Aliminase In The
Treatment Of Active Ulcerative Colitis Protocol No. 9084
Study Specifications
Protocol Number 9084
Xxxxxxxxxx Contact Xxxxxxx (Xxxx) Xxxxx, D.V.M.
PPD Pharmaco Contact Xxxxx Xxxxxx, Director, Business
Development
Compound Aliminase
Indication Active Ulcerative Colitis
Program Phase II
Study Design Double-Blind, Randomized, Placebo-
Controlled, Safety &
Efficacy Study
Number of Screened Patients 350
Number of Enrolled Patients 280
Number of Completed Patients 280
Number of Investigators 40
Investigators Meeting Yes, 94 attending
Approximate Number of
Qualification Visits 40
Type of IRB Local & Central
Number of Initiation Visits 40
Approximate Number Patients
Per Site 9
Enrollment Period 7.7 Months
Enrollment Rate .9 Patients/Month
Duration of Patient
Participation 1.5
Months
Interim Monitoring Frequency Q6-8 Weeks
Number of Interim Visits
(excluding closeout visits) 7 Per
Site (280 total)
Number of Close Out Visits 40
Estimated Number of Case
Report Form (CRF) Pages
Per Patient 26
Estimated Number of Unique
Pages Per CRF 16
Estimated Number of CRF
Pages for Data Entry 7,280
Number of Statistical Tables 38
Number of Statistical Listings 26
Number of Statistical Figures 2
Deliverable Clinical Statistical Report
PROJECT TIMELINES
Project Milestone Periods
The program timeline is summarized in the table below.
Activity
Study Initiation Jan. 1, 1999 - Mar. 30, 1999
Investigator Meeting February 1999
Enrollment Period * Mar. 31, 1999 - Nov. 25, 1999
Treatment Period Mar. 31, 1999 - Jan. 10, 1999
Study Closeout Jan. 11, 1999 - Feb. 10, 2000
Biostatistics Feb. 11, 2000 - Mar. 25, 2000
Clinical Statistical Report Mar. 26, 1999 - May 5, 2000
Total PPD Pharmaco Commitment -16.2 Months
* Any extension to the enrollment period will result in contract
modifications.
STATEMENT OF SERVICES
The following lists the specific responsibilities assigned to Xxxxxxxxxx
() or PPD Pharmaco ().
TASK LIST Xxxxxxxxxx PPD Pharmaco
A. IND/IDE
1. Prepare IND/IDE sections
2. Review IND/IDE applications
3. Submit IND/IDE to FDA
4. Prepare Investigator Brochure
B. Protocol
1. Design Study
2. Write Protocol
3. Approve Protocol
4. Prepare template informed consent
C. Case Report Form (CRF)
1. Design and draft CRFs
2. Finalize CRFs
3. Print and bind CRFs
4. Distribute CRFs to sites
5. Write CRF instruction guide
D. Site/Investigator Identification and Qualification
1. Develop list of potential sites/investigators
2. Select Study sites/investigators
3. Conduct site qualification visits
4. Provide written site evaluation reports
5. Discuss grant payments and contract with sites
6. Negotiate investigator grants, LOA, LOI
7. Prepare investigator contract
E. Pre-Study Activities
1. Collect regulatory documents (CVs, IRB approval, 1572)
2. Obtain IRB approval
3. Review & evaluate for completeness all elements of informed
consents for all sites
4. Contract with central laboratory
5. Set up project tracking system via RTMS
F. Test Article Management
1. Provide Study drug
2. Package Study drug
3. Label Study drug
4. Distribute Study drug to site
5. Store Study drug
6. Develop Drug Log
7. Manage Drug Records
8. Perform post-Study Study drug accountability
9. Destroy Study drug
10. Return unused supplies/Study drug to Xxxxxxxxxx
G. Communications Management
1. Establish and test e-mail link
2. Attend Sponsor meetings
H. Investigators Meeting
1. Plan investigators meeting(s)
2. Prepare start-up information binders
3. Approve start-up information binders
4. Conduct investigators meeting(s)
5. Present at investigators meeting(s)
I. Study Initiation
1. Conduct site initiation visits
2. Provide and maintain site training of personnel
3. Review source documents - CRFs, Drug Records, etc.
J. Patient Recruitment
1. Develop and execute advertising plan N/A
2. Refer potential patients to sites N/A
K. Project Management
1. Provide weekly updates via RTMS[TM]
2. Contribute Study information for monthly newsletter
3. Produce and distribute monthly newsletter to sites
4. Coordinate with central laboratory
5. Establish and maintain toll-free "Hot Line" N/A N/A
6. Establish and maintain 24 hour SAE phone line
7. Administer Investigator payments
8. Develop/Maintain Protocol Deviation database
9. Train the project team
L. On-Site Monitoring
1. Conduct interim on-site monitoring visits
2. Review & verify 100% of available source documentation on all CRFs
3. Review Drug Records
4. Maintain site training of personnel
5. Conduct Study closeout visits
6. Provide written site monitoring reports
M. Site Management
1. Maintain phone log of clinical questions
2. Maintain phone log of questions regarding CRFs/logistics
3. Participate in scheduled conference calls
4. Provide document control of CRFs - log, track, archive
5. Perform pre-clinical review of CRFs N/A N/A
6. Perform clinical review of CRFs
7. Perform records management
N. Database Design
1. Design data collection system
2. Develop data collection system
3. Validate data collection system
O. Data Entry
1. Design data collection system
2. Develop data collection system
3. Validate data collection system
4. Enter and verify data
P. Data Management
1. Develop data cleaning system
2. Validate data cleaning system
3. Run edit system
4. Resolve edit questions
5. Document corrections to CRFs
6. Perform DM audits on data - electronic data compared to paper CRFs
7. Provide drug dictionary
8. Code laboratory values
9. Code concomitant drugs
10. Provide adverse event dictionary
11. Code adverse events
12. Integrate/merge lab data
Q. Data Transfers
1. Format data according to Xxxxxxxxxx format (SAS datasets)
2. Perform test data transfer
3. Perform final data transfer
R. Statistical Analysis
1. Provide Analysis Plan (mock tables, listings & graphs)
2. Produce and validate tables, listings and figures
3. Provide final analysis
S. Clinical/Statistical Reports
1. Provide draft Study report
2. Provide final Study report
3. Approve Study reports
4. Provide annual report
5. Retain final electronic data
6. Retain final electronic Study report (Xxxxxxxxxx)
T. Regulatory Activities
1. Conduct GCP site audit(s)
2. Archive final Study documents
3. Record and process SAEs
U. Safety
1. Perform adverse event investigation
2. Assign adverse event causality
3. Maintain unblinding responsibility
4. Prepare SAEs reports for reporting to regulatory agency submission
5. Report serious adverse events to regulatory agency
PROJECT TEAMS
* Clinical Project Team
PPD Pharmaco's clinical team (1 Project Manager, and 4 Clinical
Research Associates) will be dedicated to this project. The following
staffing chart for clinical management and monitoring of this Study is
based on the assumptions provided in the request for proposal dated 15-
October-1998. This staffing will be in effect from the initiation
through the closeout of the Study, providing the information contained
in the Request for Proposal is consistent with forecasted project
specifics. Should the proposal assumptions change, staffing will be
reviewed and modified accordingly, after appropriate discussions with
Xxxxxxxxxx.
Proposed Clinical Project Team for Protocol 9084:
* Data Management Project Team
PPD Pharmaco will provide a full data management project team complete
with a project leader. The project leader acts as the primary contact
person for all data management aspects of this project.
Proposed Data Management Project Team for Protocol 9084:
DESCRIPTION OF SERVICES
Please refer to the Statement of Services for those activities to be
conducted by PPD Pharmaco. Should Xxxxxxxxxx require, PPD Pharmaco
would be pleased to provide a cost estimate for additional services.
Protocol
* Preparation of Protocol
Should assistance be required, PPD Pharmaco has an experienced team of
individuals who are available to provide Protocol preparation/finali-
zation for Xxxxxxxxxx.
* Informed Consent
PPD Pharmaco will provide Xxxxxxxxxx with a draft Informed Consent form
containing all 14 required elements for their review and approval prior
to submission to Ethics Committee by the Investigator.
Case Report Form (CRF)
* CRF Design
PPD Pharmaco in collaboration with Xxxxxxxxxx will design and draft the
CRF for Protocol 9084. A clinical project leader, biostatistician and
CDM manager will be consulted on the design and content. The CRFs will
be designed to capture all pertinent information in a format that
allows for rapid review and data entry.
* Print CRF
Following a final review by Xxxxxxxxxx, PPD Pharmaco will print the
copies of the Case Report Form on 3-ply NCR paper and ship to the
investigator sites prior to initiation of the Study.
Site/Investigator Identification and Evaluation
* Site/Investigator Identification
PPD Pharmaco maintains an active Investigator Recruitment Database
(IRDB) consisting of more than 16,500 investigators worldwide. The
information collected on each investigator includes: site demographics,
professional profile, specialty certifications, research profile, staff
personnel, facilities on site, data management experience, practice
setting, research experience/interest and previous clinical trial
experience. Post Study evaluations are also on file for investigators
who have worked with PPD Pharmaco. The Study Monitor and the Project
Manager complete these evaluations. This is a dynamic database that is
continually expanded and updated. It is from this database, as well as
from Sponsor lists and other external sources, that PPD Pharmaco
derives a list of potential investigators for any particular Study.
PPD Pharmaco will work closely with Xxxxxxxxxx on all aspects of
identifying the most appropriate investigators.
Some of the areas of Physician Specialty and the number of
investigators in our database include: Allergy/Immunology 240;
Anesthesiology 300; Cardiology 493; Dermatology 436; Endocrinology 184;
Family Practice 508; Gastroenterology 466; Geriatric Medicine 96;
Infectious Disease 261; Internal Medicine 3,473; Medical Oncology 276;
Neurology 479; OB/GYN 347; Orthopedic Surgery 104; Pediatrics 413;
Psychiatry 623; Surgery 305; and Urology 150.
The type and number of practice settings include: University Hospital
1,071; Other Hospital 742; Private, Solo, Group and Multi-Specialty
combined 3,675; Nursing Home 135; VA/Military 351; TMO 446; Student
Health Center 85; Urgent Care Center 124; Rehabilitation
Hospital/Clinic 135; Mental Health Mental Retardation 87; Managed
Health Care 243; and Surgical Center 159.
PPD Pharmaco will identify investigators with a proven clinical Study
record in managing and overseeing ulcerated colitis. Investigators
will be chosen on their ability to provide both the necessary patient
population and the appropriate Study staffing. Upon Xxxxxxxxxx s
approval, PPD Pharmaco will select 40 sites, and each site will recruit
approximately 9 patients during the 7.7months of anticipated
enrollment, an average of 1.2 patients/site/month.
* Select Study Sites/Investigators
When the list of potential investigators has been compiled and passed
through appropriate review by Project Management and Xxxxxxxxxx,
our project monitors will begin the process of recruiting the
investigators. Rigorous telephone screening of potential investigators
is performed by monitors prior to the on-site evaluation visits to
determine their interest in, and suitability for, performing the Study.
These telephone calls to prospective sites will allow an initial
screening via assessment of critical factors such as availability,
staff, facilities, patient population and clinical trial experience in
the appropriate therapeutic area.
The success of most programs is dependent upon the ability to identify
the most qualified investigators who will be able to enroll a
sufficient number of patients who meet criteria as specified by the
Study Protocol and to provide quality data. PPD Pharmaco, in
collaboration with Xxxxxxxxxx, will use reasonable efforts and due
diligence to ensure that each investigator selected is qualified to
perform the services required.
* Site Qualification Visits
Clinical research associates (CRAs) on the project team who have site
evaluation experience will conduct comprehensive on-site visits to
further evaluate the investigative site, meet with the Study personnel,
review the Protocol, develop the patient recruitment plan, visit all
the facilities required by the Protocol and review any other site
qualifications deemed critical to the successful completion of the
Study. The evaluator will then make final recommendations to the
project team.
PPD Pharmaco will perform the site qualification visits. The purpose
of each visit will be to assess the Study facilities, the staff and the
Principal Investigator for actual Protocol competency. During the
visit, the PPD Pharmaco project team will ensure the following:
* The Principal Investigator's expertise
* The availability of knowledgeable support staff
* The adequacy of the facility to conduct a clinical trial
* The availability of the appropriate subject population
* The Principal Investigator's understanding of the regulatory
obligations as outlined on the FDA Form 1572 and specified
by Xxxxxxxxxx and PPD Pharmaco
Written trip reports will be prepared and submitted to Xxxxxxxxxx with
the monthly status reports.
* Investigator Grants Coordination
PPD Pharmaco will, in accordance with the investigator contract
previously approved by Xxxxxxxxxx, make all necessary payments to the
investigator. Prior to payment, the Project Manager will verify the
patient enrollment status at the site to ensure all payments are
accurate and reflective of Study site activity.
Pre-Study Activities
* Regulatory Document Collection
PPD Pharmaco will collect and review all regulatory documents required
under the United States Code of Federal Regulations (CFR) for each
participating investigator. Critical documents for each site include
the following:
* Protocol agreement page
* IRB approval letter together with a list of IRB members
* A copy of the IRB-approved informed consent form to be used in
the Study
* A signed FDA Form 1572
* Curriculum vitae for the principal and sub-investigators
* Laboratory certification and normal values
Regulatory packets will be assembled and delivered to Xxxxxxxxxx.
Xxxxxxxxxx shall submit all regulatory packets to the FDA. Once the
appropriate regulatory documents have been submitted to the FDA, then
Xxxxxxxxxx will authorize shipment of the Study drug to each
individual site. PPD Pharmaco would be happy to provide regulatory
review of documents for authorization of Study drug shipment and
submission of regulatory packet to the FDA. Should this service be
requested, PPD Pharmaco would provide an estimate of these costs.
* Central Laboratory Coordination
PPD Pharmaco will coordinate with the central laboratory, which will
be ACM Medical Laboratory as designated by Xxxxxxxxxx.
Miscellaneous Clinical Supplies Management
* Miscellaneous Clinical Supplies Management
PPD Pharmaco assumes Xxxxxxxxxx will coordinate the purchase and
distribution of clinical supplies to each individual site.
Communications Management
* Communications Management
PPD Pharmaco can provide electronic communications for e-mail, file
transfer and direct system access to meet a wide variety of Sponsor
needs. Internally all PPD Pharmaco employees have Internet access via
a gateway to the Internet for external e-mail and file transfer
connectivity. PPD Pharmaco can provide dial-in or dial-out solution
using 28.8 modems either to our LAN environment or directly to our DEC
systems. A secured Sponsor intranet is also available to access
specific project status information can be developed using Internet
technology. In addition similar facilities can be provided using
Internet technology, or Lotus Notes for those Sponsors with such
capabilities.
Site/Investigators Identification and Evaluation
* Investigators Meeting
PPD Pharmaco will organize and conduct an investigators meeting
scheduled for a date to be determined. PPD Pharmaco will train the
investigators and Study coordinators on key aspects of the Study
Protocol and data collection on the CRFs. PPD Pharmaco anticipates
sending a project team of 9 members to the investigators meeting.
Moreover, PPD Pharmaco forecasts that approximately 5 members from
Xxxxxxxxxx will attend this investigators meeting. PPD Pharmaco has
based the cost estimate to execute this investigators meeting on a per
attendee fee of $1,750.00. This per attendee fee includes all travel
expenses related to the meeting, actual on-site meeting expenses and
all service fees incurred for the planning and executing of the
meeting. Payment for this service is due in full prior to the
investigators meeting and is included in the Study Payment Schedule as
a separate line item.
Study Initiation
* Site Initiation Visits
PPD Pharmaco will perform an initiation visit at each site. The
following areas will be reviewed with site personnel during the
initiation visit:
* Background information, including the Investigator Brochure
for the Study drug and/or the product package insert(s)
* Protocol, Study procedures and associated forms
* Interim monitoring visit schedule
* Regulatory requirements
* CRF and source documentation
* CRF completion instructions
* Adverse event (AE) reporting
* Study drug accountability
Training of all relevant site personnel will occur at this visit and on
an ongoing basis throughout the trial. Xxxxxxxxxx agrees that training
shall be the primary responsibility of PPD Pharmaco.
A total of 40 initiation visits will be conducted. Trip reports will
be prepared within two weeks after each visit and sent to Xxxxxxxxxx.
Project Management
* Project Management
A Project Manager will be assigned for the duration of the project and
will serve as the central contact person. The Project Manager s
responsibilities will include managing the technical and administrative
aspects of the Study as defined by Xxxxxxxxxx. The Project Manager
will coordinate the organization, implementation and management of the
Study. In addition, the Project Manager will interact directly with
the Clinical Project Director, Medical Director, Project CRAs, Quality
Assurance personnel, Data Management personnel, Medical Writing
personnel and Biostatistics to ensure the effective and timely
completion of the Study.
The Project Manager will also perform the following project-specific
activities:
* Project planning
* Preparation of the Study Operations Manual
* Coordination and assistance with personnel training
* Coordination of the investigator meeting, to include travel
and agenda planning
* Provision of monthly status reports to include:
- Regulatory document collection
- Site start-up status
- Enrollment status
- Monitor visit reports
- Site drug inventories
- Serious Adverse Events (SAEs)
- Number of CRFs retrieved
* Review and sign timesheets, expense reports, and travel
authorization
* Review travel itinerary, trip reports, external correspondence
and telephone reports, internal correspondence, follow-up
letters, monthly travel calendars/plans and project
staffing and utilization
* Assure all tracking logs are updated by the CRAs weekly
* Facilitate all financial and contractual matters between
Xxxxxxxxxx and PPD Pharmaco (i.e. prepare Study specific
invoices for payment at milestones met by PPD Pharmaco)
This Agreement does not include the cost of travel of project team
members to Xxxxxxxxxx'x offices for meetings during the conduct of this
Study. Travel costs for these meetings will be billed at invoice
total plus a nominal administration fee. At Xxxxxxxxxx'x request an
estimate will be provided.
On-Site Monitoring
* On-Site Monitoring
Xxxxxxxxxx requests that PPD Pharmaco perform all interim monitoring
visits for this Study. Given the anticipated Study length of 1.5
months per patient, an enrollment period of 7.7 months and a monitoring
frequency 6-8 weeks, PPD Pharmaco will be required to perform
approximately 7 interim monitoring visits of 1-2 days duration per
site. The CRA will perform the following tasks during each interim
visit:
* Compare 100% of the CRFs to the source documents
* Review the CRFs and source documents for serious adverse events
* Perform drug accountability
* Ensure appropriate signed informed consent form exists for each
Study participant
* Review investigator Study files for completeness
* Ensure investigator compliance to the Study Protocol
A total of 280 interim visits will be conducted. Trip reports will be
prepared after each visit and sent to Xxxxxxxxxx.
* Closeout Visits
A final closeout visit will be conducted after all subjects have
completed or have been discontinued from the Study and after all
queries have been resolved. Each visit will include:
* Review and retrieval of all outstanding CRFs
* Study drug accountability and preparation for the shipment of
Study drug to Xxxxxxxxxx
* Review of investigator's Study file for completeness
* Review of record retention per FDA requirements
A total of 40 closeout visits will be conducted. Closeout visit
reports will be prepared within two weeks after each visit and sent to
Xxxxxxxxxx.
* Total Number of Visits
Site Visits Per Site Total
Qualification 1 40
Initiation 1 40
Interim Monitoring 7 280
Closeout 1 40
TOTAL 13 400
Site Management
* In-House Site Management by Clinical Project Team
Between monitoring visits, investigators will be called weekly to
verify patient enrollment status, review Study progress, answer
Protocol questions, discuss CRF completion and ensure the Study
proceeds in a timely manner. Site contact reports will become part of
the investigator file located at PPD Pharmaco. Additionally the PPD
Pharmaco CRAs will be responsible for:
* Tracking and ordering Study drug and other supplies
* Tracking regulatory document revisions
* Writing trip reports
* Writing follow-up letters
* Providing query resolution
* Performing in-house second review of CRF s
* Participating in scheduled conference calls with Xxxxxxxxxx
* Tracking Protocol violations, CRF progression at site and
PPD Pharmaco and tracking of query resolution
* Conducting audit of investigator files at PPD Pharmaco
* Developing newsletter materials and distributing the
newsletter to sites
PPD Pharmaco will be responsible for all follow-up on action items
identified during the monitoring visits.
* Clinical Review of CRFs and Query Resolution
The CRF will be forwarded to the Clinical Project Manager or their
designee who will evaluate the following elements:
* Accurate and appropriate documentation of AEs
* Overall subject Study drug and Protocol compliance
* Proper identification and documentation of potential Protocol
deviations or violations
* Accurate completion of inclusion/exclusion criteria
* Accurate transcription of CRF data
* Appropriate use of medical terminology
* Correlation of all clinical information
* Accuracy of any medication dosages
The findings of the clinical review will be documented and forwarded to
the Project CRAs for resolution.
Data Management
* Data Management Plan
The CDM Project Manager will compile a Data Management Plan that
describes the processes and specifications to be used in the project.
This includes documentation on the data dictionary; coding dictionaries
to be used; the logic and processes for data review and validation;
critical timelines and milestones; and timing and types of management
reports. This Plan will be reviewed and finalized with input from
Xxxxxxxxxx and will be updated during the course of the project.
* Database Development
Unless otherwise requested, the project database will be set up using
ORACLE 7/Clintrial 3.3. The CRF and Protocol will be used to develop
the specifications for this database. Panel definitions and field
specifications will be produced by an experienced data manager
utilizing the PPD Pharmaco standard Clintrial dictionary.
Xxxxxxxxxx'x database specifications will be used if so desired.
Specifications will be independently reviewed prior to installation.
* Data Entry
Data entry screens and multiforms will be developed in Clintrial
against the standard data dictionary, but customized to the Study CRF
requirements. Independent, double data entry will be performed. The
entry of the data from each CRF into the database will take place as
CRFs are retrieved, to keep the database as current as possible. All
data entry discrepancies will be resolved by PPD Pharmaco data
management staff. Reports regarding data entry status and the
database will be available as needed.
* Data Validation
Validation (edit) checks and derivation procedures will be developed
by PPD Pharmaco using SQL, RPL, or SAS procedures. The validation
specifications will be developed taking into account the requirements
of the analysis plan, a review of the Protocol and general experience.
The validation specifications will be forwarded to Xxxxxxxxxx for
review and approval. The results from the validation process will be
reviewed and queries will be generated for resolution.
* Importing Electronic Data
Electronic data from central laboratories or other sources and any
associated ranges will be imported and integrated into the Study
database. PPD Pharmaco will provide validation checks as required and
produce flagged listings as part of the data management and
statistical reporting process.
* Coding of Drugs and Diseases
Unless otherwise requested by Xxxxxxxxxx, PPD Pharmaco will provide
the coding dictionaries required for coding adverse events and
concomitant medications. COSTART will be used to code adverse events
and WHODRUG will be used to code concomitant medications. PPD
Pharmaco will use its ORACLE-based autoencoding system to identify
appropriate codes and insert them into the appropriate tables. The
PPD Pharmaco autoencoding system maintains a synonym dictionary so as
not to compromise Xxxxxxxxxx'x dictionaries. This synonym dictionary
also contains multi-lingual coding translations. Efficient support of
international and cross-national coding schemes is provided.
Validation checks on the synonym code lists can be imposed to insure
that coding meets Sponsor criteria. A final clinical review will be
conducted of all codes to ensure accuracy and consistency.
* Data Query Resolution Process
Queries arising from data entry, validation and dictionary coding will
be reviewed and, if possible, resolved by Data Management personnel,
according to the rules documented in the Data Management Plan. Where
necessary, queries will be passed to PPD Pharmaco CRAs for resolution
or forwarded to the investigator. Review and correction of data will
occur on an ongoing basis. Edits resulting from the responses to
query forms will be updated and verified before being stored in the
database. Queries and corrections will be tracked electronically for
each CRF.
* Status Reports
PPD Pharmaco will provide Xxxxxxxxxx with standard monthly status
reports indicating the progress made on the project. This report can
be customized to meet Xxxxxxxxxx'x specifications. The report will
include such information as number of patients entered, number of
completed patients, number of ongoing patients and metrics on key
processes.
* Data Management Auditing
To ensure accuracy, PPD Pharmaco will carry out a 100% review of all
key safety and efficacy variables. In addition, a random 10% of the
CRFs will undergo a 100% verification against the database throughout
the Study. Various patient listings are also produced and reviewed to
additionally assure data quality and consistency.
* Final Database
A final quality assurance (QA) audit will be performed on 10% of the
patients on the final database after the quality control measures have
been completed. A written report of the QA audit will be prepared and
sent to Xxxxxxxxxx reporting discrepancies that are found.
PPD Pharmaco standard database delivery is in a SAS format; however,
it will be provided in another format if Xxxxxxxxxx so chooses. The
program code will remain with PPD Pharmaco at the conclusion of the
Study. CRFs and supporting documentation will be returned to
Xxxxxxxxxx at the conclusion of the project.
* Data Transfers
* Format and Test. PPD Pharmaco will require data transfer
specifications (i.e. file layouts, formats) before initiating
program development for data transformation. PPD Pharmaco
recommends at least one preliminary transfer to test the transfer
mechanisms prior to the final database transfer.
* Final. PPD Pharmaco will provide Xxxxxxxxxx with computer files
containing the project database(s) along with complete
documentation.
Statistical Analysis
* Biostatistics Project Team
Within the Biostatistics department, a Lead Biostatistician will
oversee all analyses and production of tables and listings. This
person will be responsible for providing the appropriate analysis,
instructing the team on key data issues and interacting with the
Sponsor as well as other PPD Pharmaco groups, and/or regulatory
authorities. Support Statisticians will work closely with the Lead
Statistician to assure compliance with the analysis plan. PPD
Pharmaco will also identify a Lead Statistical Programmer who will
oversee the resourcing of tables, figures and listings in production.
Furthermore, validation efforts under the direction of a primary
Validator will insure the accuracy of the results. All results will
be reviewed by a QC Auditor prior to release to the Sponsor. This
core team will provide the Sponsor with a dedicated team to
efficiently implement the statistical analysis.
* Biostatistics Services Overview
The proposed biostatistics workscope for this programs includes
collaboration with data management on CRFs and edit checks, a
statistical analysis plan, 1 interim analysis, a final statistical
a n alysis and biostatistical collaboration on a final clinical
statistical report. All of PPD Pharmaco's statistical services and
procedures are designed for compliance with the ICH Draft Guideline on
Statistical Principles for Clinical Trials (Federal Register, Vol. 62,
No. 90, 9 May 1997). The proposed services and deliverables are
described in greater detail in the following sections.
* Biostatistics Collaboration with Data Management
PPD Pharmaco's Biostatistics team will begin to access data to create
the analysis datasets once a sufficient amount of data has been
entered. In addition to standard validation checks that are
programmed by the Data Management group, exploration of data problems
or issues that affect statistical analysis will be considered.
Statisticians will work closely with the Data Managers and Clinical
Project Leaders to discuss relevant issues to improve ongoing data
collection efforts.
* Analysis Plans
In collaboration with the Sponsor's assigned clinical and statistical
scientists, PPD Pharmaco will develop one analysis plan for the Study.
Any analysis strategy features unique to the Study will be explained
in the analysis plan in detail. The analysis plan will model the
final Study reports; the introduction, background, objectives and
statistical methodology sections will be written in sufficient detail
for the final reports. This advance writing and planning promotes
earlier, more detailed, critical thinking about the analysis needs and
reduces writing time and costs for the final reports.
The analysis plan will include shells for the final Study report
tables, figures and listings. The shells will be developed based on
Protocol objectives, the analysis strategy and collaborative input
from the Sponsor's clinical and statistical scientists. The shells
will show concisely how statistical summaries are to be presented on
the page. Each custom table layout will be designed to promote a
complete, consistent and concise representation of analysis for the
Study's results.
The cost of the Analysis Plan is based on the following assumptions:
* One draft version and one final version of the analysis plan text
and shells are budgeted.
* The Analysis Plan will include each unique table template and
with each template, the list of tables that are to be based on
that template. Also included will be listing and figure shells.
* Analysis and Reporting Databases
PPD Pharmaco will develop an analysis and reporting database, based on
written specifications developed by the biostatistics team.
The written specifications for the analysis database will include a
detailed description of each component analysis file, including
information about how the file relates to other files in the database,
a dictionary of included variables (showing assigned formats and
labels) and detailed specifications for each created variable included
in the file. The specifications for each created variable include
the following components: variable name, format, label, a prose
description of the variable, the source variables required for its
creation, and the logic algorithms used in its creation.
* Statistical Analysis and Tables Production
Analogous to the specifications for the analysis database, PPD
Pharmaco will develop detailed specifications for the statistical
analyses and tables production. PPD Pharmaco will design, create and
validate SAS? programs that perform the analyses described in the
analysis plan and the summary tables and listings. The internal
documentation components for the analysis and table production will
include the analysis plan, tables and listings specifications,
documented SAS? analysis programs, resulting SAS? output for the
analyses and documentation of the validation/QC of the tables and
listings. PPD Pharmaco will provide documentation of all created
variables used in any analysis or data summary.
Where practical, PPD Pharmaco will use SAS? macros to facilitate
consistent application of the analysis strategy across all Protocols.
Some proprietary SAS? macros will be used as well, particularly for
summaries of safety information and for table formatting. While
proprietary macros will not be made available to the Sponsor, a
description of their design intent can be provided for any audit
review. All SAS? programs used or generated for this project will
remain the property of PPD Pharmaco.
The cost of the statistical analyses and tables production is based on
the following assumptions:
* The estimated counts for tables, listings and figures are summarized
as follows:
Counts Uniques Repeats Total
Tables 22 16 38
Listings 23 3 26
Figures 2 0 2
* Additional unique tables will be provided at a cost of $2,000 per
table and additional listings will be provided at a cost of $1,000
per listing.
* Table production costs will be based on the approved analysis
plan and table shells.
* Any Sponsor-requested changes after analysis plan approval should
be communicated in writing through the project director.
Discussions about the changes may precede the written authorization,
as needed, to clarify and cost the request in advance. Sponsor-
requested changes made after the approval may require additional
costs and may affect the production timetable.
* The scope of this bid allows for one review of draft tables.
* Statistics Report
A statistical report will be prepared which contains a brief review of
the clinical trial methodology and will report the statistical
findings of the analysis. The report will also contain a description
of the statistical methodology suitable for inclusion in the
statistical methods section of the final report as well as a technical
statistical methodology write up for inclusion in the statistical
appendix of the final report.
Regulatory activities
* Good Clinical Practice (GCP) Audits
PPD Pharmaco will conduct 4 trial site regulatory compliance audits.
The purpose of each trial site audit is to determine the trial site s
adherence to the Study Protocol and Good Clinical Practices (GCP)
guidelines and Federal Regulations; to ensure integrity of scientific
data; to determine that the rights and welfare of human research
subjects are being or have been adequately protected; and to ensure
that PPD Pharmaco and the Sponsor have monitored the trial site in
accordance with GCPs, Federal Regulations, and standard operating
procedures. Trial site selection will be based on several Study
variables: sites with high or rapid enrollment, sites with a
significant number of Protocol violations, sites with a frequent
change in Study personnel, or sites with noticeably better/worse
efficacy and safety data compared to other investigators within the
Study. Normally, 10% to 20% of trial sites participating in a
clinical Study are audited to ensure general regulatory compliance.
Each trial site audit will involve an audit of the following: a 100%
review of regulatory documents; a 100% review of all signed informed
consents; a 100% review of investigational material accountability; a
100% review of reported serious adverse events; an investigator and/or
Study coordinator interview; facilities inspection; and a 100%
revalidation of subject source documentation to case report forms for
15% to 25% of the subjects enrolled at a site. The number of subject
records reviewed at each trial site will depend upon the completion of
case report forms at the time of the audit.
Clinical/Statistical Reports
* Integrated Clinical and Statistical Reports
PPD Pharmaco will write a complete Integrated Clinical and Statistical
Report (ICSR) for the Study, in accordance with Sponsor specifications
and current ICH guidelines. In initial preparation of the ICSR, prior
to completion of the final analyses, PPD Pharmaco will create a report
shell using the Study Protocol and records of Study conduct. The
Sponsor has the option to review and approve the shell. When the final
analysis results are available, PPD Pharmaco project management,
medical writers, biostatisticians, therapeutic experts and the Sponsor
will interact to discuss the interpretation of the data and to develop
the discussion section of the ICSR. The results will then be
incorporated into the shell and PPD Pharmaco will provide a draft
report for review by the Sponsor.
Following review by the Sponsor, a round table discussion of the report
may be held. The goal of the round table is to achieve consensus on
and ensure a complete understanding of Sponsor comments prior to
finalization of the ICSR. If a round table discussion is not held, the
Sponsor must provide only one set of comments to PPD Pharmaco for
incorporation into the final ICSR. When the round table discussion has
concluded, or when Sponsor comments have been received by PPD Pharmaco,
the final version of the ICSR will be generated and submitted to the
Sponsor for approval.
All ICSRs written by PPD Pharmaco will undergo a complete internal
review by a Quality Control Coordinator, the project statistician, the
project manager, the project physician, and a Quality Assurance Auditor
prior to release to the Sponsor. This review will consist of a review
of format against the Sponsor style guide, verification of compliance
with ICH guidelines, a 100% comparison of data, both tabular and in
text, against listings and tables, and a medical/scientific review of
data interpretation.
One draft of the ICSR will be provided to the Sponsor for review
and comment. Additional review cycles will result in delays in
finalization and increased costs. Review of the draft by the Sponsor
should not exceed two weeks time. Any time beyond this period will
result in an equal delay in finalization of the report.
Safety
* Serious Adverse Event Reporting and Monitoring
Investigative sites will report all serious adverse events (SAEs)
directly to PPD Pharmaco. PPD Pharmaco will ensure that each event
has been properly recorded on the SAE form. Once initial review has
been completed, PPD Pharmaco will fax the SAE report to Xxxxxxxxxx.
The procedure should be completed within one working day of receipt of
an SAE report.
It is understood that Xxxxxxxxxx'x medical monitors will review all
SAEs and determine causality. PPD Pharmaco's Medical Monitor will be
responsible for reviewing the SAE report for accuracy and completeness
and for answering routine clinical questions.
PPD Pharmaco's MA/PVG group will be responsible for preparing patient
SAE narratives for IND Safety Report. All patient narratives will be in
a format acceptable to both PPD Pharmaco and Xxxxxxxxxx. It is assumed
that narratives will undergo only one review cycle by Xxxxxxxxxx.
Xxxxxxxxxx will be billed for this activity based on the actual number
of SAE narratives completed.
PROJECT BUDGET
BUDGET SUMMARY FOR Xxxxxxxxxx PROTOCOL 9084:
TASK
1. Clinical*** 1,212,061
2. Data Management 164,335
3. Biostats* 93,447
4. Medical Writing 40,731
5. Regulatory: File & Site Audits 84,203
6. Medical Monitoring 7. 46,207
SAE Narratives will be separately
invoiced at the rate of $875.00 each
7. IS Support 17,707
Total Direct Costs $1,658,690
Investigator Meeting Preparation 153,000
Investigator Grants** 773,640
IRB Reimbursement 18,850
Central Labs 29,921
Travel - Monitoring 415,833
Travel - Site Audits 6,152
CRF Printing and Shipping 5,459
Miscellaneous 431
Total Indirect Costs $1,403,287
Project Grand Total $3,061,977
* Additional unique tables or figures will be provided at a cost of
$2,000 per table or figure and additional listings or repeat tables
or repeat figure will be provided at a cost of $1,000 each.
** Sponsor will be billed an additional $1,448 for each screening
failure.
*** Figure includes additional labor expenses incurred due to the delay
in the availability of drug.
