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EXHIBIT 10.6
CLINICAL DEVELOPMENT AGREEMENT
PROTOCOL #VIT-02-08961X AND PROTOCOL #VIT-03-08961X: Two Phase III Safety and
Efficacy Studies of Vitrase(TM) (Hyaluronidase for Ophthalmic Intravitreal
Injection) for Clearance of Severe Vitreous Hemorrhage.
PREPARED FOR: Advanced Corneal Systems, Inc.
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BY: Covance Clinical and Periapproval Services Inc.
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20 October 1998
[COVANCE LOGO]
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CLINICAL DEVELOPMENT AGREEMENT
THIS AGREEMENT, made as of the date last signed below is by
and between ADVANCED CORNEAL SYSTEMS, INC., a corporation of the State of
California having its principal place of business at ▇▇▇▇▇ ▇▇▇▇▇ ▇▇▇▇▇▇▇, ▇▇▇▇▇
▇▇▇, ▇▇▇▇▇▇, ▇▇▇▇▇▇▇▇▇▇, ▇▇▇▇▇ ("ACS"), and COVANCE, INC., doing business as
COVANCE CLINICAL AND PERIAPPROVAL SERVICES, INC., a corporation of the State of
Delaware having its principal place of business at ▇▇▇ ▇▇▇▇▇▇▇▇ ▇▇▇▇▇▇,
▇▇▇▇▇▇▇▇▇, ▇▇▇ ▇▇▇▇▇▇ ▇▇▇▇▇-▇▇▇▇ ("COVANCE").
WITNESSETH:
WHEREAS, ACS is an ethical pharmaceutical manufacturer which is
currently considering the evaluation of the safety and effectiveness of a drug
known as Hyaluronidase Solution (the "DRUG") for the clearance of severe
vitreous hemorrhage; and
WHEREAS, COVANCE is in the business of providing services for the
development of experimental new drugs in North and South America, Asia,
Australia, and Europe; and
WHEREAS, ACS has entered into a contract substantially similar to this
Agreement with CroMedica Global, Inc. ("CROMEDICA"), for the purpose of having
CroMedica assist ACS with the execution of substantially the same clinical
investigation of the DRUG in South Africa ("CROMEDICA STUDY") and ACS intends to
enter into a contract substantially similar to this Agreement with Verum
Staticon ("VERUM"), for the purpose of having Verum assist ACS with the
execution of substantially the same clinical investigation of the DRUG in
Germany ("VERUM STUDY"); and
WHEREAS, ACS desires to contract with COVANCE, and COVANCE desires to
be contracted by ACS, for the purposes of providing such services to assist ACS
in the execution of a clinical investigation of the DRUG and the preparation of
the data (incorporating the result's from both COVANCE's clinical investigation,
the CROMEDICA STUDY, and the VERUM STUDY) into a report or reports for ACS to
submit to the United States Food and Drug Administration ("FDA") and other
international regulatory authorities for marketing approval (collectively the
"SUBMISSIONS") and completion of other tasks as outlined in Exhibit A,
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NOW, THEREFORE, the parties hereby agree as follows:
1. Obligations of Covance: COVANCE hereby agrees to conduct a clinical
investigation (the "STUDY") of the DRUG in accordance with ACS's
instructions and the accepted standards of medical and clinical
research standards. The services to be provided by COVANCE to ACS will
include, but will not be limited to, the following:
(a) COVANCE will conduct the STUDY in accordance to agreed upon
protocols and as outlined in Exhibit A. The STUDY will be
conducted in full compliance with this Agreement and in
accordance with the protocol, any protocol amendments mutually
agreed to by the parties, any conditions set forth by the
reviewing Institutional Review Board ("IRB") and all
applicable Federal, state, and local laws, statutes,
ordinances, and regulations including all applicable
regulations enforced by the FDA for the conduct of clinical
trials used to support marketing approval of the DRUG. COVANCE
also agrees that Investigators will agree to conduct the study
in accordance with generally accepted standards of Good
Clinical Practice.
(b) COVANCE will include the data received from CroMedica and
Verum in connection with the CROMEDICA STUDY and VERUM STUDY
in the SUBMISSIONS or parts thereof, prepared by COVANCE.
COVANCE will be responsible for the timely and proper
preparation of the SUBMISSIONS or parts thereof COVANCE will
not be responsible for any delays, and/or deficiencies that
are caused by CROMEDICA's or VERUM's failure to implement the
agreed to PROTOCOLS or deliver the data from the CROMEDICA
STUDY or VERUM STUDY to COVANCE in accordance with mutually
agreeable timelines or in a mutually acceptable format;
provided, however, that COVANCE has provided ACS with timely
notice of potential delays and/or deficiencies once it has a
reasonable basis to believe either or both are likely.
(c) COVANCE will recruit qualified investigators identified by ACS
("INVESTIGATOR") with the necessary and appropriate experience
and standing to perform the STUDY; and said INVESTIGATOR must
be licensed to practice medicine in the location where the
STUDY is to be conducted and must be in compliance with
21 CFR 312.53.
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(d) COVANCE will prepare necessary and appropriate documentation
for submission to the appropriate regulatory authority and ACS
for the conduct of the STUDY including but not limited to the
following:
1) A completed and signed Form FDA-1572
2) Current curriculum vitae of the INVESTIGATOR and all
secondary INVESTIGATORS identified on Form FDA-1572.
3) PROTOCOL (defined below) signature page signed by the
principal INVESTIGATOR.
4) A copy of the informed consent form to be used by the
INVESTIGATOR.
5) IRB's (defined below) approval of the PROTOCOL and
informed consent form.
For purposes of this Agreement: (i) "IRB" means an
institution review board that complies with the
requirements of Title 21, Part 56 of the code of
Federal Regulations, as amended, supplemented or
modified from time to time; and (ii) "PROTOCOL" means
the document which specifies the testing procedures
and conditions mutually agreed upon by ACS and
COVANCE for the performance of a STUDY.
6) As appropriate, IRB approval of PROTOCOL amendments
and annual re-approvals.
(e) COVANCE will undertake to assure that INVESTIGATORS hereby
certify that they have not been debarred under the provisions
of the Generic Drug Enforcement Act of 1992, 21 U.S.C. 306 (a)
or (b). In the event that INVESTIGATOR:
(i) becomes debarred; or
(ii) receives notice of action or threat of
action with respect to their debarment,
during the term of this Agreement, COVANCE
and INVESTIGATOR agree to notify ACS
immediately. In the event that
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any INVESTIGATOR becomes debarred as set
forth in clause (i) INVESTIGATOR understands
that this Agreement shall automatically
terminate without any further action or
notice by either party. In the event that an
INVESTIGATOR receives notice of action or
threat of action as set forth in clause
(ii) above, COVANCE and INVESTIGATOR
understands that ACS shall have the right
to terminate this Agreement immediately.
(f) COVANCE hereby certifies that they have not and will not
knowingly use in any capacity the services of any individual,
corporation, partnership or association which has been
debarred under 21 U.S.C. 306 (a) or (b). In the event that
COVANCE or any INVESTIGATOR becomes aware of the debarment or
threatened debarment of any individual, corporation,
partnership or association providing services to COVANCE or an
INVESTIGATOR which directly or indirectly relate to
Investigator's activities under this Agreement, COVANCE and
INVESTIGATOR shall notify ACS immediately. COVANCE and
INVESTIGATOR understand that ACS shall have the right to
terminate this Agreement immediately upon receipt of such
notice.
(g) COVANCE will provide all INVESTIGATORS with the current
INVESTIGATORS' brochure and any amendments thereto and, as the
investigation proceeds, will keep each INVESTIGATOR informed
of new information received from ACS regarding the DRUG.
(h) COVANCE will monitor the STUDY in accordance with all now or
hereafter applicable Federal, state, and local laws, statutes,
ordinances, and regulations, including without limitation:
Food and Drug Administration (or any other government body or
agency that succeeds it) ("FDA") guidelines on the
responsibilities of sponsors, monitors and clinical
INVESTIGATORS and informed consents in compliance with Good
Clinical Practices.
ACS shall have the right, but not the obligation, to
co-monitor, in conjunction with COVANCE, the INVESTIGATORS
retained by COVANCE and their STUDY with respect to the
services provided hereunder. In the event ACS determines there
is cause for independent monitoring by ACS, it may do so
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following prior written notification to COVANCE, and COVANCE
will assist and cooperate with ACS therein.
(i) COVANCE agrees that throughout the duration of this Agreement,
and at any subsequent time when COVANCE shall receive
information regarding the safety of the DRUG used in the STUDY
as it pertains to serious or unexpected adverse experiences,
it shall notify ACS in writing, in English. Such notification
shall be in such a timely fashion so as to permit full
compliance with all regulatory requirements (e.g. 21 CRF
312.32) for the handling and disclosure of any information
concerning any serious or unexpected event, injury, toxicity
or sensitivity reaction or any unexpected incidence, or the
severity thereof, associated with the clinical use, studies,
investigations, tests, whether or not determined to be
attributable to the DRUG. "Serious," as used in this section,
refers to an experience at any dose which results in death or
which places the patient at immediate risk of death,
in-patient hospitalization or prolongation of existing
hospitalization, a persistent or significant disability or
incapacity, a congenital anomaly, cancer or birth defect, or
an important medical event that may jeopardize the patient and
may require medical or surgical intervention to prevent any of
the foregoing outcomes, or as such definition may otherwise be
amended, supplemented or modified from time to time by the
FDA. "Unexpected," as used in this section, refers to
conditions or developments to the frequency, specificity or
severity of which are not consistent with the current
investigator brochure or, if an investigator brochure is not
required or available, with the risk information described in
the general investigational plan or elsewhere in the current
application or conditions or developments that have not been
previously observed during clinical studies of the DRUG, or as
such definition may otherwise be amended, supplemented or
modified from time to time by the FDA.
ACS and COVANCE shall be responsible for collecting,
reporting, and processing all relevant serious and unexpected
adverse experience ("SAE") information and follow-up SAE
information as defined in the SAE Reporting Plan developed by
ACS and Covance.
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(j) COVANCE will collect the evidence related to the safety of the
drug as it is obtained from the INVESTIGATORS being monitored
by COVANCE and forward such evidence to ACS.
(k) COVANCE will store copies of all data and records in
accordance with local and FDA regulations. The originals of
all such information will be forwarded to ACS at the
termination of the program.
(1) COVANCE will report to ACS any INVESTIGATOR that is not
complying with his/her signed agreement (Form FDA-1572) and
attempt to obtain compliance. If compliance is not promptly
obtained and after approval is received from ACS, Covance will
end the INVESTIGATORS participation in the STUDY, and recover
any DRUG and STUDY records.
(m) COVANCE will be responsible for the selection of monitors
qualified by training and experience to monitor the progress
of the investigation.
(n) ACS will undertake the shipment of the DRUG to participating
INVESTIGATORS, During the STUDY, COVANCE will monitor to
ensure that the clinical INVESTIGATOR maintains a record of
the dates and amounts of drug supplies received at the STUDY
location; the dates, amount and patients to whom the test DRUG
has been administered; the dates (when known) and amount of
the drug broken, spilled, or lost; and the dates and amount of
the DRUG supply which is being returned. At the completion or
early termination of each STUDY, COVANCE will make an
accounting of all clinical supplies. COVANCE will assure that
the INVESTIGATOR shall return to ACS (or to another location
specified by ACS), after the completion or earlier termination
of any such STUDIES all unused DRUG supplies and account for
all DRUG supplies which have been lost or missing.
(o) Should appropriate regulatory authorities or any other
Federal, state, or local government authority conduct, or give
notice of intent to conduct, an inspection at any
investigational site or take any other regulatory action with
respect to services provided for in this Agreement, then
COVANCE will promptly give ACS notice
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thereof, supply all information pertinent thereto, and ACS
shall have the right, but not the obligation, to be present at
any such inspection or regulatory action.
2. Transfer of Obligations: Pursuant to 21 CFR 312.52, ACS has
transferred to COVANCE all of the obligations identified in Attachment
1 and agrees that the same description and extent of obligations
transferred should be included in Form FDA 1571, Section #13. COVANCE
accepts the transferred responsibilities and agrees to carry out
diligently all transferred obligations. All obligations not
specifically transferred hereunder are retained by ACS.
3. Status Reporting: All of the hereinabove described services shall be
performed in close cooperation with ACS, and designated ACS personnel
will be kept continuously informed of the progress of the
INVESTIGATIONS.
COVANCE will provide status reports on the STUDY. The status reports
will include, but not be limited to: the number of patients entered,
dropped, and completed in the STUDY. Reports of monitoring visits will
also be provided on a timely basis as specified in Exhibit A.
4. Clinical Supplies: ACS will, at its expense, supply the INVESTIGATORS
with the DRUG and other DRUG supplies as are agreed upon by COVANCE and
ACS for the timely completion of the STUDY hereinabove described, and
will direct the shipment of any such supplies to the location indicated
by COVANCE, within a reasonable time after receipt of notification from
COVANCE of the need for any such clinical supplies.
5. Confidential Information: COVANCE agrees that all materials, documents
and information provided to it by ACS and, except as provided in
Section 14, all information developed by COVANCE exclusively in
connection with the STUDY, whether prior or subsequent to the execution
of this Agreement, for ACS pursuant to this Agreement is and shall be
considered as confidential information to ACS (collectively, the
"CONFIDENTIAL INFORMATION") and the sole property of ACS. COVANCE
agrees to hold such CONFIDENTIAL INFORMATION in strict confidence for
ten (10) years after the date of this Agreement and shall disclose the
CONFIDENTIAL INFORMATION to hospital authorities, IRB, INVESTIGATORS
and their respective agents, employees, officers and directors, and
representatives only on a need-to-know
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basis (including fulfilling corporate reporting obligations) and only
if the foregoing parties (other than hospital authorities and IRBs) are
bound and obligated by the same provisions of confidentiality as used
by any member of COVANCE; provided that (a) COVANCE will have no
obligations with respect to any CONFIDENTIAL INFORMATION that is now or
later becomes publicly available through no fault of COVANCE, (b)
COVANCE obtains such CONFIDENTIAL INFORMATION from a third party
entitled to disclose it, (c) COVANCE can demonstrate through written
records it already has in their possession such CONFIDENTIAL
INFORMATION as indicated in their written records, or (d) such
CONFIDENTIAL INFORMATION is required by any law, rule, regulation,
order, decision, decree or subpoena or other judicial, administrative
or legal process to be disclosed.
All obligations of confidentiality and non-disclosure set forth in this
Agreement will survive, without limitation, the expiration or earlier
termination, for any reason, of this Agreement.
Nothing contained in this Section 5 shall be interpreted to limit the
rights of COVANCE and ACS's obligations under Section 14 hereof and to
the extent that any conflict arises in applying the provisions of
Sections 5 and 14, the provisions of Section 14 shall control.
Upon the completion or earlier termination of this Agreement, COVANCE
will promptly return to ACS all of the CONFIDENTIAL INFORMATION, as
well as all written material which incorporates any CONFIDENTIAL
INFORMATION.
COVANCE acknowledges that the disclosure of CONFIDENTIAL INFORMATION
without ACS's express written permission will cause ACS irreparable
harm and that the breach or threatened breach of the nondisclosure
provisions of this Agreement will entitle ACS to injunctive relief, in
addition to any other legal remedies that may be available to it.
6. Compensation:
(a) Attached hereto as Exhibit A are the COVANCE Time and Cost
Estimates, which contains the budgets for out-of-pocket costs
and for COVANCE costs, which can only be modified by the
procedure described in this Section.
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(b) ACS hereby agrees to pay COVANCE for all services performed by
COVANCE and its agents and clinical investigators pursuant to
this Agreement, as set forth in Exhibit A, provided that the
total amount paid by ACS shall not exceed the cost estimates
provided for in Exhibit A, unless agreed to in writing by the
parties or allowed for in this Section.
(c) All direct COVANCE out-of-pocket expenses incurred on behalf
of ACS, such as, but not limited to travel and shipping
expenses, do not have profit factors applied to them. COVANCE
expects that the specified out-of-pocket costs estimated in
Exhibit A will be correct to within 10%. ACS agrees to this
margin of the estimate as long as expenses are based on actual
costs and documented. If changes in the program occur that
affect out-of-pocket costs, or COVANCE otherwise projects that
costs may exceed the estimates plus 10%, COVANCE will provide
revised estimates for ACS's review and written approval as
specified in Section 8.
Out-of-pocket costs will be invoiced to ACS on a monthly
basis. These invoices will contain summary reports of
expenses. Receipts of all expenses will remain on file at
COVANCE and will be open to ACS inspection, if requested.
(d) COVANCE fees for this project will not exceed those specified
in Exhibit A unless there is a change in the program agreed to
in writing by the parties and documented as described in
Section 8.
COVANCE fees will be invoiced in accordance with the payment
schedule outlined in Attachment 2.
(e) ACS will, within thirty (30) days subsequent to the date of
this Agreement, pre-pay COVANCE an amount corresponding to 25%
of the out-of-pocket costs of the project over the first 12
months as contained in Exhibit A. This amount will be adjusted
to correspond to the next 12 month period each successive year
of the program.
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This prepaid amount will be returned to ACS at the early
termination or completion of the project or credited against
final invoices as agreed to between COVANCE and ACS.
(f) COVANCE will submit to ACS a monthly invoice approximately
twenty (20) days after the end of each calendar month during
the term of this Agreement that will contain out-of-pocket
costs as specified in Section 6(b) and (c). Invoices for
COVANCE fees will be provided as specified in Section 6(d).
All invoices are payable within thirty (30) days of receipt.
(g) All payments or prepayments by ACS under Section 6 shall be
made free of interest.
7. Assumptions:
(a) The time, cost, fee and budget estimates specified in Exhibit
A with respect to a STUDY are subject to a number of general
and STUDY specific assumptions. The general assumptions
(collectively, the "GENERAL ASSUMPTIONS") are as follows:
(i) The scope of the STUDY remains constant;
(ii) ACS and COVANCE execute all of their obligations
under this Agreement in a timely manner;
(iii) ACS and Covance fully cooperate with each other in
the performance of their obligations under this
Agreement and refrain from any actions or inactions
which prevent a party from timely or properly
performing its obligations hereunder and thereunder,
respectively; and
(iv) No other event outside of COVANCE's or ACS's control,
including, without limitation, the events described
in Section 10 occur.
The STUDY specific assumptions (the "STUDY SPECIFIC
ASSUMPTIONS") are set forth in Exhibit A.
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(b) In the event that any of the ASSUMPTIONS (defined below) are
not complied with by the parties or the parties desire to
modify or deviate (a "DEVIATION") from them, or the parties
determine that the STUDY objectives cannot be fulfilled based
on the ASSUMPTIONS, then the budget, fees, costs and time
estimates for such STUDY as specified in Exhibit A shall be
modified in accordance with the terms of Section 8 hereof. For
purposes of this Agreement, "ASSUMPTIONS" means any of the
GENERAL ASSUMPTIONS and the STUDY SPECIFIC ASSUMPTIONS.
8. Change Orders:
(a) In the event a DEVIATION is identified by ACS or COVANCE, the
identifying party shall notify in writing the other party of
such DEVIATION. Within 20 business days from the receipt by
COVANCE or sending of such DEVIATION notice, COVANCE shall
provide ACS with an estimate of the modification to the
timeline, costs and fees and overall budget (whether an
increase or decrease) arising from such DEVIATION. ACS shall
have seven business days to approve such modification
estimates. If ACS does not approve such modification estimates
and has not terminated the STUDY but wants the STUDY to be
modified to take in account the DEVIATION, then ACS and
COVANCE shall use their best efforts to agree on modification
estimates that are mutually acceptable.
(b) During the DEVIATION ASSESSMENT PERIOD (defined below),
COVANCE shall continue work on the STUDY if practicable but
shall not implement the modification representing the
DEVIATION unless approved in writing by ACS.
For purposes of this Agreement, "DEVIATION ASSESSMENT PERIOD"
means the time from the date COVANCE sends or receives a
notice of DEVIATION pursuant to this Section 8 and the date
ACS either accepts or rejects COVANCE's modification estimates
as specified in this Section 8.
9. Early Termination: ACS may terminate this Agreement prior to the
STUDY's completion at any time for any reason upon 30 days written
notice to COVANCE. In the event of such termination, COVANCE shall be
promptly paid in full for all work and services performed in connection
with such STUDY, including all out-of-pocket expenses and all
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COVANCE fees, as of the date work on such STUDY is actually concluded.
COVANCE shall use all reasonable efforts to conclude or transfer the
STUDY as expeditiously as practicable and in accordance with all
applicable laws, rules and regulations, including those of the FDA.
Further, COVANCE and ACS shall cooperate with each other during such
STUDY termination to safeguard patient safety, continuity of patient
treatment and to comply with applicable laws, rules and regulations.
In addition to the costs, expenses and fees specified in this
Section 9, ACS shall pay to COVANCE an amount equal 1.5 (months) times
the average of the monthly fee paid to COVANCE during the STUDY (x
dollars), as liquidated damages and not as a penalty; provided that
such fee shall not be paid if ACS has terminated the STUDY because of
COVANCE's breach of a material obligation under this Agreement.
10. Force Majeure. The parties shall be excused from performing their
obligations under this Agreement if its performance is delayed or
prevented by any event beyond such party's is reasonable control,
including, but not limited to, acts of God, fire, explosion, weather,
disease, war, insurrection, civil strife, riots, government action or
power failure, provided that such performance shall be excused only to
the extent of and during such disability. Any time specified for
completion of performance in this Agreement falling due during or
subsequent to the occurrence of any such events shall be automatically
extended for a period of time equal to the period of such disability.
COVANCE will promptly notify ACS if, by reason of any of the events
referred to herein, COVANCE is unable to meet any such time for
performance specified in this Agreement.
11. Indemnity - Clinical Investigators: ACS hereby agrees to indemnify and
hold harmless the INVESTIGATORS, subject to limitations (a), (b), (c),
(d) and (e) below, from and against any and all costs (including costs
and reasonable attorneys' fees), expenses, damages and judgments
resulting from a claim which occurs to a participant in the STUDY which
was directly or indirectly caused by the DRUG provided:
(a) The conduct of the INVESTIGATOR is not negligent or otherwise
tortisus;
(b) ACS is properly notified in writing of the claim, but no
indemnitee shall lose indemnification rights hereunder by
failing to give the indemnifying party such
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notice unless such failure materially and adversely affects
the indemnifying party's ability to defend;
(c) ACS is given sole and absolute control of, and discretion in,
the handling of such claim, action or suit, including, without
limitation, the selection of defense counsel, provided ACS
reasonably and promptly acknowledges its intent to assume
control of the defense of such claim, action or suit;
(d) ACS receives the full cooperation of the INVESTIGATOR during
pendency of the claim or lawsuit; and
(e) The STUDY is conducted in full accordance with the PROTOCOL,
any PROTOCOL amendment, and in accordance with generally
accepted medical standards; slight deviations arising out of
necessity and not contributing to the injury or affecting the
STUDY validity shall not be considered a failure to adhere to
the PROTOCOL.
12. Indemnification - COVANCE:
(a) COVANCE shall indemnify and hold harmless ACS and its
officers, directors, employees and agents from any loss,
damage, cost or expense (including reasonable attorney's
fees) (a "LOSS") arising from any claim, demand, assessment,
action, suit or proceeding (a "CLAIM") for personal injury to
STUDY participants or personal injury to any employee of ACS
or property damage arising or occurring during the conduct of
the STUDY as a result of COVANCE's negligence, gross
negligence or intentional misconduct or inaction or
performance that violates the law; provided that if such LOSS
or CLAIM arises in whole or in part from ACS's negligence,
gross negligence or intentional misconduct or inaction, then
the amount of the LOSS that COVANCE shall indemnify ACS for
pursuant to this Section 12 shall be reduced by an amount in
proportion to the percentage of ACS's responsibilities for
such LOSS as determined by a court of competent jurisdiction
in a final and non-appealable decision or in a binding
settlement between the parties.
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(b) ACS shall indemnify and hold harmless COVANCE, and their
respective affiliates and their respective officers,
directors, employees and agents (the "COVANCE GROUP") from any
CLAIM or LOSS arising from or related to (i) personal injury
to a participant in the STUDY or personal injury to any
employee of the COVANCE GROUP directly or indirectly caused by
the DRUG, (ii) this AGREEMENT, the STUDY or any aspect thereof
set forth in the PROTOCOL that violates any applicable law,
rule, regulation or ordinance, (iii) the DRUG's harmful or
otherwise unsafe effect, including, without limitation, a
CLAIM based upon ACS's or any other person's use, consumption,
sale, distribution or marketing of any substance, including
the DRUG, or (iv) the negligence, gross negligence or
intentional misconduct or inaction of ACS in the performance
of its obligations under this AGREEMENT or the PROTOCOL
related to such STUDY (v) the performance of CROMEDICA or
VERUM in its obligations; provided that if such LOSS or CLAIM
(other than a LOSS or CLAIM described in clause [iii] hereof
arises in whole or in part from COVANCE's negligence, gross
negligence or intentional misconduct or inaction or COVANCE's
violation of the law, then the amount of such LOSS that ACS
shall indemnify the COVANCE GROUP for pursuant to this Section
12 shall be reduced by an amount in proportion to the
percentage of COVANCE's responsibilities for such LOSS as
determined by a court of competent jurisdiction in a final and
non-appealable decision or in a binding settlement between the
parties. ACS shall not indemnify the COVANCE GROUP from any
LOSS or from any CLAIM described in clause (iii) hereof
arising solely from the willful misconduct or inaction or
gross negligence of COVANCE or COVANCE's violation of the law.
(c) Upon receipt of notice of any CLAIM which may give rise to a
right of indemnity from the other party hereto, the party
seeking indemnification (the "INDEMNIFIED PARTY") shall give
written notice thereof to the other party, (the "INDEMNIFYING
PARTY") with a CLAIM for indemnity. Such CLAIM for indemnity
shall indicate the nature of the CLAIM and the basis
therefore. Promptly after a CLAIM is made for which the
INDEMNIFIED PARTY seeks indemnity, the INDEMNIFIED PARTY shall
permit the INDEMNIFYING PARTY, at its own option and expense,
to assume the complete defense and settlement of such CLAIM,
provided that (i) the INDEMNIFIED PARTY will have the right to
participate in the defense of any such CLAIM at its own cost
and
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expense, (ii) the INDEMNIFYING PARTY will conduct the defense
of any CLAIM with due regard for the business interests and
potential related liabilities of the INDEMNIFIED PARTY. The
INDEMNIFYING PARTY will not, in defense of any such CLAIM,
except with the consent of the INDEMNIFIED PARTY, consent to
the entry of any judgment or enter into any settlement which
does not include, as an unconditional term thereof, the giving
by the claimant or plaintiff to the INDEMNIFIED PARTY of a
release from all liability in respect thereof. As to those
CLAIMS with respect to which the INDEMNIFYING PARTY does not
elect to assume control of the defense, the INDEMNIFIED PARTY
will afford the INDEMNIFYING PARTY an opportunity to
participate in such defense, at the INDEMNIFYING PARTY's own
cost and expense, and will not settle or otherwise dispose of
any of the same without the consent of the INDEMNIFYING PARTY.
(d) The obligations of the parties under this Section 12 shall
survive the termination of this AGREEMENT.
13. Default: If COVANCE is in default of its material obligations under
this Agreement, then ACS shall promptly notify COVANCE in writing of
any such default. COVANCE shall have a period of thirty (30) days from
the date of receipt of such notice within which to cause the cure of
such default. If COVANCE shall fail to so cause such cure, or if such
failure cannot be cured within the specified cure period, then this
Agreement shall, at ACS's option, immediately terminate. In the event
of such termination, ACS's sole remedy shall be, a reduction in the
total contract price for the Services in an amount equal to the
difference between (i) the total contract price for the Services and
(ii) the value of the work properly performed; provided, however, that
under no circumstances shall COVANCE be liable to ACS in an amount
that, in aggregate, exceeds, the contract price paid for the Services,
as specified in this Agreement. UNDER NO CIRCUMSTANCES SHALL ACS BE
ENTITLED TO INCIDENTAL, INDIRECT, CONSEQUENTIAL OR SPECIAL DAMAGES
ARISING IN CONNECTION WITH SUCH DEFAULT OR BREACH OF COVANCE'S
OBLIGATIONS UNDER THIS AGREEMENT.
14. Property Ownership. All materials, documents, data, information and
suggestions of every kind and description supplied to COVANCE by ACS
or prepared or developed by COVANCE pursuant to this Agreement (except
for COVANCE procedural manuals,
17
20 October 1998
Page 16
personnel data, and COVANCE-developed computer software, technology or
Covance's Interactive Voice Response System used for patient drug
randomization) shall be the sole and exclusive property of ACS and ACS
shall have the right to make whatever use it deems desirable of any
such materials, documents and information; provided that COVANCE may
retain copies of such materials as required by applicable laws, rules
and regulations. Unless otherwise required by law or by the terms of
this Agreement, all such ACS property which COVANCE shall have in its
possessions shall be maintained by COVANCE for a period of not less
than three (3) years from the date of receipt thereof and shall be
organized in such manner that it will be ready for immediate reference.
After three (3) years or such longer period as may be required by
applicable laws or regulations, COVANCE may dispose of such property in
accordance with ACS's instructions. If ACS fails to give said
instructions, COVANCE shall so notify ACS; and if said instructions are
still not forthcoming within thirty (30) days of said notification,
then COVANCE may destroy such property as it determines.
15. Recruitment
(a) ACS agrees that it will not solicit or otherwise encourage
COVANCE employees to seek employment with ACS throughout the
term of this Agreement.
(b) COVANCE agrees that it will not solicit or otherwise encourage
ACS employees to seek employment with COVANCE throughout the
term of this Agreement.
16. Patent Rights: COVANCE shall not acquire any rights of any kind
whatsoever with respect to ACS's product as a result of performance
under this agreement or otherwise. All inventions, discoveries, and
technology relating to the ACS product, whether patentable or not,
conceived by COVANCE or its employees or agents, including the
INVESTIGATORS or their employees or agents, solely or jointly with
others as a result of work done under this Agreement, shall be, and
remain at all times the sole and exclusive property of ACS. COVANCE
will disclose promptly to ACS or its nominee any and all patentable
inventions, discoveries and improvements conceived or made by COVANCE
as a result of providing such services to ACS pursuant to this
Agreement and relating to such services, and agrees to assign all its
interest therein to ACS or its nominee; provided, ACS requests such
assignment within one year of notification of such invention; provided,
further, that COVANCE shall retain all rights to any data, processes,
18
20 October 1998
Page 17
software (including codes) technology, means, know-how developed by
COVANCE which relate to data collection, data management or to
Covance's Interactive Voice Response System used for patient drug
randomization (IVRS data and programming). Whenever requested to do so
by ACS, COVANCE will execute any and all applications, assignments, or
other instruments and give testimony which ACS shall deem necessary to
apply for and obtain Letters of Patent of the United States or of any
foreign country or to protect otherwise ACS's interests therein, and
ACS shall compensate COVANCE for the time devoted to said activities
and reimburse it for expenses incurred. COVANCE agrees to include in
agreements with INVESTIGATORS participating in the STUDY, a provision
requiring such INVESTIGATORS to assign to ACS on terms substantially
similar to this Section 16 patentable inventions, discoveries and
improvements made by such INVESTIGATORS during the STUDY. These
obligations shall continue beyond the termination of this Agreement and
shall be binding upon COVANCE's assignees, administrators and other
legal representatives.
17. Modifications: No changes may be made in this Agreement except by
written agreement of both parties.
18. Entire Agreement: This Agreement, together with any attached
Exhibit(s), is the entire and complete understanding of the parties in
regard to the covered subject matter. It replaces, supersedes and
renders void any and all predecessor agreements between the parties
whether written or oral.
19. Independent Contractor: COVANCE's relationship with ACS under this
Agreement shall be that of an independent contractor, and nothing in
this Agreement or the arrangements for which it is made shall
constitute COVANCE, or anyone furnished or used by COVANCE in the
performance of the services contemplated by this Agreement, as an
employee, joint venture, partner, or servant of ACS.
20. Contact with ACS: Until further notice, COVANCE's contacts within ACS
will be ▇▇▇ ▇▇▇▇▇▇▇▇ and ▇▇▇▇▇ ▇▇▇▇▇▇ or such persons as said ▇▇.
▇▇▇▇▇▇▇▇ or ▇▇. ▇▇▇▇▇▇ shall designate.
21. Notices: Any notices which either party may be required or shall desire
to give hereunder shall be deemed to be duly given when delivered
personally or mailed by certified or
19
20 October 1998
Page 18
registered mail, postage prepaid, to the party to whom notice is to be
given at the address first given above or such other address or
addresses of which such party shall have given written notice.
22. Severability: If any provisions hereof shall be determined to be
invalid or unenforceable, the validity and effect of the other
provisions of this Agreement shall not be affected thereby.
23. Governing Law: This Agreement is a New Jersey contract. It shall be
governed and construed and interpreted in accordance with the laws of
New Jersey without giving effect to its choice of law principles.
24. Waiver: The waiver by either party or the failure by either party to
claim a breach of any provision of this Agreement shall not be deemed
to constitute a waiver or estoppel with respect to any subsequent
breach or with respect to any provision thereof.
25. Term of Agreement: This Agreement shall become effective on the date
last signed below and shall continue until midnight on the 30th day of
September, 2004, unless modified as provided for herein.
26. Captions. Any caption used in this Agreement is inserted for
convenience and reference only and is to be ignored in the construction
and interpretation of the provisions hereof.
COVANCE INC.
(d/b/a COVANCE CLINICAL AND
ADVANCED CORNEAL SYSTEMS, INC. PERIAPPROVAL SERVICES, INC.)
By: /s/ [ILLEGIBLE] By: /s/ [ILLEGIBLE]
----------------------------- --------------------------------
Title: President & CEO Title: Corporate VP & GM
-------------------------- -----------------------------
Date: October 24, 1998 Date: 3 November, 1998
--------------------------- ------------------------------
20
EXHIBIT A.1
ACS: HYALURONIDASE SOLUTION
PROTOCOL #VIT-02-08961X AND PROTOCOL #VIT-03-08961X
TIME AND COST ESTIMATE
21
ADVANCED CORNEAL SYSTEMS
A Revised Time and Cost Estimate for Assistance with
the Conduct of Two Global Phase III Studies of
Vitrase(TM) (Hyaluronidase for Ophthalmic
Intravitreal Injection) for Clearance of Severe
Vitreous Hemorrhage
PREPARED FOR-
Advanced Corneal Systems, Inc.
▇▇▇▇▇ ▇▇▇▇▇ ▇▇▇▇▇▇▇, ▇▇▇▇▇ ▇▇▇
▇▇▇▇▇▇, ▇▇▇▇▇▇▇▇▇▇ ▇▇▇▇▇
PREPARED BY-
Covance Clinical and Periapproval Services Inc.
▇▇▇▇ ▇▇▇▇▇ ▇▇▇▇▇▇▇▇▇▇ ▇▇▇▇▇▇▇▇▇, ▇▇▇▇▇ ▇▇▇
▇▇▇▇▇▇ ▇▇▇▇▇, ▇▇▇▇▇▇▇▇▇▇ ▇▇▇▇▇
10 July 1998
10 September 1998 (revision)
20 October 1998 (revision)
22
TABLE OF CONTENTS
I. Introduction 1
II. Project Scope and Timelines
Project Scope 3
Project Timelines 4
III. Responsibilities and Services
ACS and Covance Responsibilities 5
Pre-Study Preparation 7
Site Identification and Qualification 10
Study Drug Management 13
Site Initiation, Monitoring, and Management 14
Serious Adverse Event Reporting 17
Project Management 18
Data Management 20
Statistical Analysis 23
Clinical Trial Report Preparation 23
NDA Preparation 24
IV. Cost Estimates 25
Appendices
Appendix 1: Covance's Interactive Voice Response System
Appendix 2: Covance's Trial Tracker System
Appendix 3: Covance Pharmaceutical Packaging Services Estimate
MATERIAL CONTAINED IN THIS PROPOSAL IS CONFIDENTIAL
AND IS THE PROPERTY OF COVANCE, INC.
23
I. INTRODUCTION
Advanced Corneal Systems (ACS) has requested that Covance Clinical and
Periapproval Services, Inc. (Covance) revise and update the 10 September
1998 Time and Cost Estimate for assistance in conducting two global Phase
III Studies of Vitrase(TM) (Hyaluronidase for Ophthalmic Intravitreal
Injection) for Clearance of Severe Vitreous Hemorrhage.
This revised proposal contains a detailed summary of the scope of work to
be performed by Covance, task assumptions, and cost estimates. We have
made adjustments to reflect the following changes:
- Covance will not be responsible for preparing and submitting the NDA
- An increase in the monitoring hours during the enrollment period from 10
to 16 hours per visit
- Inclusion of Brazilian IND costs
The changes above are in addition to the previous changes in scope from
Covance's July 1998 Time and Cost Estimate, which include:
- Covance will not be responsible for preparing the Canadian IND and the
European MAA
- A decrease in the number of Quality Assurance site audits from 30 to 15
audits
- An increase in the number of pre-study site evaluation visits from 114
to 123 visits
- A net increase in the number of initiated investigative sites from 120
to 145 sites
- 36 more sites in the United States
- 7 more sites in France
- 1 more site in the Netherlands
- 2 more sites in the United Kingdom
- 6 less sites in Canada
- 5 less sites in Brazil
- 10 less sites in South Africa
- A net increase in the number of productive sites from 80 to 105 sites
- An increase in the number of monitoring days from 1,284 to 2,365 days
- An increase in the number of case report form pages per patient from 32
to 36 pages. However, Covance has assumed a higher level of efficiency in
data management, which results in lower overall data entry costs.
Advanced Corneal Systems 20 October 1998
Vitrase(TM) 1
24
- South African sites may participate in this study after completing the
Phase II study. If required, costs for conducting this Phase III study
and for drug supply management in South Africa will be provided at a
later time.
COSTS HAVE NOT BEEN INCLUDED WITHIN THIS TIME AND COST ESTIMATE FOR THE
GERMAN CRA MONITORING SERVICES AND RELATED OUT-OF-POCKET EXPENSES, AS ACS
WILL BE RESPONSIBLE FOR CONTRACTING AND MAINTAINING THE CONTRACT AND
PAYMENTS WITH THE CRA.
This Time and Cost Estimate, based on discussions with ACS, describes
Covance's plan for supporting the Vitrase(TM) Phase III program. The
Project Scope and Timeline section outlines the program scope and
timelines. The Responsibilities and Services section provides a detailed
summary of organizational responsibilities and task assumptions. Cost
estimates appear in Section IV. Changes to timelines, organizational
responsibilities, or program assumptions listed in this Time and Cost
Estimate may have an impact on the costs indicated. Details regarding
Covance's Interactive Voice Response System, Trial Tracker System, and
Covance Pharmaceutical Packaging Services are provided as appendices.
Advanced Corneal Systems 20 October 1998
Vitrase(TM) 2
25
II. PROJECT SCOPE AND TIMELINES
PROJECT SCOPE
Two Phase III, randomized, masked safety and efficacy studies
of Vitrase(TM) for the treatment of severe vitreous hemorrhage
will be conducted under separate protocols. Protocol #
VIT-02-08961X will be conducted at 80 investigative sites in
North America (United States and Canada). Protocol #
VIT-03-08961X will be conducted at 60 investigative sites in
Europe and 5 sites in Brazil. All investigative sites are
stand-alone sites and are expected to enroll a minimum of 1.0
to 1.5 patients per month during a 15 month enrollment period.
In the North American study, a total of 800 eligible patients
will be randomized into one of four treatment arms in a
1:1:1:1 ratio
(1) Vitrase(TM) 7.5 IU
(2) Vitrase(TM) 55 IU
(3) Vitrase(TM) 75 IU
(4) Watchful waiting
In Europe and Brazil, 800 eligible patients will be randomized
into the same four treatment arms used in the North American
study.
While in the study, patients will be clinically evaluated at
Baseline (Day 0); Days 1, 2, and 7; and Months 1, 2, 3, 6, and
12. In addition, the FDA has requested bi-annual follow-up
visits over a three year period (Months 18, 24, 30, 36, 42,
and 48). Costs for activities for the follow-up period will be
provided in a separate proposal. Table 1 provides a summary of
the project specifications.
TABLE 1
VITRASE(TM) PHASE III STUDY SPECIFICATIONS
-----------------------------------------------------------------------------------------
Number of Patients Enrolled 800 (North America) and 800 (Europe and Brazil)
Number of Initiated Sites 80 (North America) and 65 (Europe and Brazil)
Number of Productive Sites 60 (North America) and 45 (Europe and Brazil)
Case Report Form Size(a) 36 pages per patient
Enrollment Rate(b) Approximately 1.0 to 1.5 patients per site per month
Enrollment Period(b) 15 months
Final Deliverable 4 Integrated Clinical/Statistical Reports
- 3 Months (2 studies)
- 12 Months (2 studies)
-----------------------------------------------------------------------------------------
(a) CRF size specified by ACS
(b) Enrollment rate and period projected by ACS
Advanced Corneal Systems 20 October 1998
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PROJECT TIMELINES
Table 2 presents the assumed timelines for the Vitrase(TM)
Phase III program.
TABLE 2
ESTIMATED TIMELINES
-----------------------------------------------------------------------
MILESTONE DATE
-----------------------------------------------------------------------
Planning Activities Start July 1998
Investigator Screening July - September 1998
Regional Investigators' Meetings October 1998 and January 1999
First Patient Enrolled October - November 1998
Last Patient Enrolled January 2000
Last Patient Out (3 months) April 2000
Delivery of 3 Month Clinical Study July 2000
Reports
Last Patient Out (1 Year Follow-Up) January 2001
Delivery of 1 Year Follow-Up May 2001
Clinical Study Reports
-----------------------------------------------------------------------
o Timeline provided by ACS and apply to each study
Advanced Corneal Systems 20 October 1998
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27
III. RESPONSIBILITIES AND SERVICES
ACS AND COVANCE RESPONSIBILITIES
Table 3 presents the responsibilities shared between ACS or its
designee (e.g., German contract CRA) and Covance to meet the objectives
of the Vitrase(TM) Phase III program. A detailed discussion of these
activities is provided after Table 3.
Table 3
Summary of Responsibilities for Vitrase(TM) Phase III Program
----------------------------------------------------------------------------
ACS COVANCE
----------------------------------------------------------------------------
Pre-Study Preparation
Protocol Preparation P S
Investigator's Brochure P
Template informed consent form development P R
Case-report form development R P
Print and ship case report forms P
CRF Completion Instructions and Site Manual R P
Study File Notebook P
Regulatory submissions (FDA, HPB and South P
African regulatory authorities)
Regulatory submissions (European and Brazilian P
regulatory authorities)
Randomization scheme P
Kick-off meeting S P
Project team training meeting S P
Site Identification and Qualification
Investigative site identification and screening (a) S P
Pre-study site evaluation visits S P
Approve final site selection P S
Regulatory document acquisition and review S P
Translations P
Negotiation and administration of investigator P
contracts
Study Drug Management
Clinical drug supply labeling and distribution
United States and Canada P
Europe, Brazil, and South Africa (b) S P
On-site clinical drug supply inventory control P
Patient randomization (IVRS) P
-------------------------------------------------------------------------------
(a) ACS has identified and screened a number of investigative sites in Europe
and North America
(b) Study drug management costs for South Africa have not been included. Costs
for these activities will be provided when the scope of work for South
Africa is fully defined
P = Primary Responsibility
S = Shared Responsibility
R = Review
Advanced Corneal Systems 20 October 1998
Vitrase(TM) 5
28
Table 3 (continued)
Summary of Responsibilities for Vitrase(TM) Phase III Study
-------------------------------------------------------------------------------------
Responsibility ACS Covance
-------------------------------------------------------------------------------------
Site Initiation, Monitoring and Management
Organization and conduct of Investigators' meetings P
Initiation visits S P
Develop clinical monitoring plan and study forms S P
Routine monitoring visits S P
Close-out visits S P
In-house site management P
Quality assurance site visits P
Serious Adverse Event Reporting
SAE Reporting Plan R P
Collect study-specific adverse event information P
Provide medical evaluation of adverse events P
Report SAEs to FDA and HPB P
Report SAEs to all European and Brazilian reg. authorities P
Report SAEs to investigative sites P
Maintain safety database P
Reconcile Safety and Clinical Databases P
Project Management
Overall project management S P
Conduct team meetings P
Conduct weekly teleconferences with ACS S P
Conduct quarterly face-to-face meetings with ACS S P
Project status reporting S P
Maintenance of study master files P
Data Management Services
Data Management Plan R P
Develop database and data entry screens P
Data processing and entry P
Data review and clean-up P
AE and concomitant medication coding P
Quality assurance of databases P
Transfer of clinical data P
CRF disposition and archival P
Statistical Analysis
Statistical Analysis Plans R P
Statistical programming and analyses P
Review tables, listings, and figures R P
Clinical Study Report Preparation
Clinical study reports (3 and 12 Month Data) R P
NDA Preparation P
-------------------------------------------------------------------------------------
Advanced Corneal Systems 20 October 1998
Vitrase(TM) 6
29
PRE-STUDY PREPARATION
PROTOCOL PREPARATION
ACS will be responsible for the development of the study protocols. Covance
will review the draft protocols and provide comments to ACS, who will be
responsible for preparing the final protocols. Covance has assumed two
review cycles for each protocol.
ACS will submit the final study protocol to the US Food and Drug
Administration (FDA) and the Canadian Health Protection Branch (HPB).
Covance will provide the final protocol to all other regulatory agencies
and all investigative sites.
INVESTIGATOR'S BROCHURE
ACS will provide the Investigator's Brochure to Covance. ACS will be
responsible for updating the Investigator's Brochure, as necessary, and
providing updates to the FDA, the HPB, and Covance. Covance will distribute
the Investigator's Brochure and subsequent updates to all other regulatory
authorities and all investigative sites.
TEMPLATE INFORMED CONSENT FORM DEVELOPMENT
ACS will prepare a template patient informed consent form (ICF) for each
study based on the ICF used in the Phase II study. Covance will review the
template and provide comments to ACS. ACS will be responsible for final
approval of the template ICF. Covance has assumed two review cycles for ICF
finalization.
In Europe and Brazil, Covance will translate the ICFs into the local
language, taking into account all country specific requirements.
Covance will interact with investigative sites in obtaining site specific
changes to the ICF in accordance with instructions provided by ACS.
CASE REPORT FORM DEVELOPMENT AND PRINTING
Covance will be responsible for designing the Phase III case report form
(CRF) for each study. To allow for rapid retrieval, review, and data entry,
Covance will design the CRFs to make use of:
- A segmented design format
- International date coding
- Completion in English
- Precoding, where applicable
Advanced Corneal Systems 20 October 1998
Vitrase(TM) 7
30
Per ACS's instructions, Covance has assumed each CRF will be 36 pages in
length, with approximately 10 to 15 unique pages. Covance will provide
draft CRFs to ACS for review and comment. Covance has assumed two review
cycles for each CRF.
Covance will print the CRFs on three-part NCR paper and ship the CRFs to
all investigative sites.
CRF COMPLETION INSTRUCTIONS AND SITE MANUAL DEVELOPMENT
To facilitate accurate completion of the CRF by the investigative sites,
Covance will prepare CRF Completion Instructions for each study. These
instructions will provide detailed procedures for completing each section
of the CRF. It will also highlight important protocol adherence items and
interrelated sections within the CRF.
Covance will also prepare a Site Manual that will include the CRF
completion instructions, monitoring frequency, query resolution
procedures, patient screening procedures, and all other forms and
procedures that are applicable for this study.
Covance has assumed the CRF Completion Instructions and the Site Manual
will be written in English and require one review cycle by ACS prior to
finalization. Covance will be responsible for printing and shipping copies
of the CRF Completion Instructions and Site Manual to monitors, study
coordinators, investigators, and ACS.
STUDY FILE NOTEBOOK
Covance will develop and forward to each investigative site a Study File
Notebook. The binder is provided to file the following documents:
- Protocol and amendments
- Protocol summary and study schema
- Investigator's Brochure
- Informed Consent Form
- Institutional Review Board or Independent Ethic Committee approvals
- Adverse event reporting procedure
- Safety updates
- FDA 1572
- Regulatory binder maintenance instructions (with signature verification
sheet and site visit log)
- Correspondence
Advanced Corneal Systems 20 October 1998
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31
Covance will be responsible for ensuring that each investigator maintains
and updates their Study File Notebook at each site.
PREPARATION OF REGULATORY SUBMISSIONS
ACS will be responsible for all initial and subsequent IND and INDs
regulatory submissions and filings to the FDA and the HPB during this
program, including all amendments and maintenance. Covance will be
responsible for all initial and subsequent regulatory submissions and
filings in Brazil, France, Germany, Italy, Poland, the Netherlands,
and the United Kingdom, including all amendments and maintenance in
support of these two Phase III clinical trials. Covance will be the
primary contact for regulatory authorities within each of these European
countries and Brazil.
RANDOMIZATION SCHEME
Covance will prepare the randomization schedule for each study and
administer central patient randomization using an Interactive Voice
Randomization System (IVRS). Covance's IVRS is described in detail in
Appendix 1.
KICK-OFF MEETING
An ACS-Covance Phase II/III kick-off meeting was held on 25 June 1998.
Discussion items at the meeting included task responsibilities, timelines,
and communication plans.
PROJECT TEAM TRAINING MEETING
To ensure consistency in understanding and implementing program objectives,
ACS's Project Physician and Covance's International Project Director will
conduct two formal training sessions for Covance's clinical project team
members. The first training session was conducted in North America on 20
July and the second training session will be conducted at the European
Investigators' Meeting. Covance has assumed members of the ACS Vitrase(TM)
Project Team will attend and contribute to each meeting.
The training session will include a review of the details of the
Vitrase(TM) program, the Investigator Brochure, disease state, and
regulatory requirements. It will also include a review the protocol, CRF
completion requirements, monitoring requirements, pharmacy instructions,
and present an overview of the pre-study requirements, adverse event
reporting requirements, and expectations for study completion and
follow-up.
Advanced Corneal Systems 20 October 1998
Vitrase(TM) 9
32
Each training session is expected to last one day and will be
videotaped for future reference. Covance and ACS will share
the responsibility for the preparation of all training
materials. All proposed training materials and plans will be
circulated between ACS and Covance for review and comment
prior to the training session.
SITE IDENTIFICATION AND QUALIFICATION
INVESTIGATIVE SITE IDENTIFICATION AND SCREENING
Table 4 summarizes the total number of site contacts,
pre-study visits, and initiation visits to be conducted by
Covance for these studies in the US, Canada, Europe and
Brazil.
TABLE 4
INVESTIGATIVE SITE IDENTIFICATION AND SCREENING
--------------------------------------------------------------
REGION SITE CONTACTS PRE-STUDY INITIATION
VISITS VISITS
--------------------------------------------------------------
United States 120 90 76
Canada 10 8 4
Europe* 0 20 43
Brazil 5 5 5
--------------------------------------------------------------
* Excludes sites located in Germany.
ACS has identified a contract CRA for the German sites who
will perform the following tasks according to Covance
standards:
- Evaluation and selection of sites including pre-study visits
and reports
- Budget and SOA negotiations
- Attendance and follow-up of Investigators' Meeting in
Brussels
- Attendance to one training meeting in Covance Brussels
- Translations
- Provide assistance to Investigators for EC submissions
- Initiation, routine monitoring, and close-out visits,
reports, and follow-up
- Provide input for status reports
- Attendance to project team meetings
- Maintenance of project files
- SAE-reporting according to the SAE plan
- Site management
- Shipping of non-drug supplies
- Tracking of investigator payments
- Assistance to the follow-up of issues raised during audits
Advanced Corneal Systems 20 October 1998
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33
- In-House review of retrieved CRFs
- Clinical query resolution with sites
- Drug/randomization code accountability on sites
Covance has assumed it will be responsible for the following activities for the
German sites:
- Regulatory submissions
- SAE Plan
- SAE reporting to authorities
- SAE reporting to Investigators and Ethics Committees (ECs)
- Notifying reportable SAEs to Central ECs
- Review and approval of Investigator regulatory document package
- Site Audits
- Drug distribution and tracking (including IVRS)
- Drug label translation and review
Table 5 provides the assumed investigative site location by country, by study,
and the assumed patient enrollment by country. The patient enrollment potential
within each country has not been confirmed by a formal feasibility study.
TABLE 5
INVESTIGATIVE SITE LOCATION AND ESTIMATED PATIENT ENROLLMENT
--------------------------------------------------------------------------------
ESTIMATED NUMBER
LOCATION SITES OF PATIENTS
--------------------------------------------------------------------------------
Study #VIT-02-08961X 80 ▇▇▇
▇▇▇▇▇▇ ▇ ▇▇
▇▇▇▇▇▇ ▇▇▇▇▇▇ 76 720
Study #VIT-03-08961X* 65 ▇▇▇
▇▇▇▇▇▇ ▇▇ ▇▇
▇▇▇▇▇▇▇ ▇▇ ▇▇▇
▇▇▇▇▇ 5 75
The Netherlands 8 ▇▇
▇▇▇▇▇▇ ▇ ▇▇▇
▇▇▇▇▇▇ ▇▇▇▇▇▇▇ 12 100
Brazil 5 125
--------------------------------------------------------------------------------
* Covance and ACS anticipates changes in the site numbers and patient enrollment
numbers.
Advanced Corneal Systems 20 October, 1998
Vitrase(TM) 11
34
PRE-STUDY SITE EVALUATION VISITS
ACS has identified 10 sites in the US and 40 sites in Europe that do not require
pre-study visits. Therefore, Covance will conduct 98 pre-study site evaluation
visits in North America, 20 pre-study visits in Europe (excluding Germany), and
5 pre-study visits in Brazil. Each pre-study visit will last ten hours including
time for preparation, travel, and report generation. At each pre-study site
visit, the Covance monitor will conduct an in-depth interview to evaluate the
investigator with respect to:
- His or her professional experience and training
- Past experience in conducting clinical trials
- Current participation in or future scheduling of studies that will compete
for patients with severe vitreous hemorrhage.
- Access to appropriate study patients
- Evidence of the number of potential patients entering the investigator's
facility on a monthly basis
- Ability to meet ACS's and Covance's enrollment goals
- Proper level of staffing, including availability of study coordinator
- Adequacy of facilities, including required study medical equipment
- Secure drug refrigeration (between 2 degrees and 8 degrees Celsius) and
storage capabilities
- Understanding of regulatory requirements
ACS may elect to co-monitor some of the pre-study site visits with the Covance
monitor.
Covance will provide a monitor's report to ACS electronically (via Covance's
Trial Tracker System) within ten working days of completing a pre-study site
visit. Covance will define the format of the pre-study visit reports.
REGULATORY DOCUMENTS ACQUISITION AND REVIEW
Covance will collect and review the required pre-study regulatory documents for
each investigative site, including Institutional Review Board (IRB) and
Independent Ethics Committee (IEC) approvals. Covance also will be responsible
for obtaining annual IRB and IEC renewals for the duration of this study.
Covance will review all documents for completeness and accuracy prior to
submission to regulatory authorities. ACS will submit regulatory documents to
the FDA, HPB, and South African regulatory authorities. Covenance will submit
regulatory documents to all other regulatory authorities in Europe and Brazil,
as appropriate.
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TRANSLATIONS
Covance will ensure accurate translations of ICFs, protocol synopsis, and
clinical drug labels into appropriate languages using
translators/regulatory affairs staff located in Covance's Canadian,
Brazilian, and European offices.
NEGOTIATION AND ADMINISTRATION OF INVESTIGATOR BUDGETS AND CONTRACTS
ACS will provide Covance with guidelines for negotiation of investigator
budgets. Covance will be responsible for negotiating the lowest reasonable
investigator budget within the guidelines provided by ACS. Covance will
discuss with ACS investigative sites that do not fall within these
guidelines. ACS will develop a standard investigator contract and payment
schedule.
ACS will be responsible for maintenance of investigator contracts and all
administrative details and payments to investigators. ACS will reimburse
investigators on a pro-rated basis for work performed according to a
written agreement. Covance will visually verify that investigators have
performed the work before payment.
STUDY DRUG MANAGEMENT
CLINICAL DRUG SUPPLY
ACS will be responsible for packaging, labeling, and shipment of study
medications in Canada, Brazil, and the United States. ACS will send
packaged drug to Covance for distribution to sites in Europe. Covance
Pharmaceutical Packaging Services (CPPS) in Horsham, UK will be responsible
for drug distribution in Europe, Brazil and South Africa. Covance will set
up and maintain import licenses where required by local regulations.
Covance also will be responsible for supplying, tracking, and shipping of
all ancillary materials.
Covance will be responsible for developing country-specific secondary
labels from the original English label text provided by ACS. The secondary
labels will also include investigator name and address, telephone number,
site number, and any local regulatory requirements. To ensure the accuracy
of the secondary labels, Covance will conduct back-translation
certification of the final labels. Covance will affix the secondary labels
before shipment of study medications to investigative sites within Europe.
Covance has assumed ACS will be responsible for all country-specific
secondary labeling activities for Canadian.
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ON-SITE CLINICAL DRUG SUPPLY INVENTORY CONTROL
During monitoring visits and at study closure, Covance will be responsible
for verifying site documentation regarding receipt of study drug and for
ensuring the investigative sites maintain proper drug dispensing records.
At the end of the study, Covance will either manage the return of study
drug to ACS and reconcile any remaining drug supplies or instruct sites to
destroy drug upon authorization from ACS.
PATIENT RANDOMIZATION
Covance proposes the use of an Interactive Voice Response System (IVRS)
for this program. The IVRS provides computerized patient randomization
using touch-tone telephone equipment and computerized voice output.
The following features will be available in this program:
- Secure site access to the IVRS through a touch-tone telephone, using a
toll-free number and individual site access code
- Patient randomization following the site's entering of specific project
and patient information, which is repeated by the system for
verification prior to randomizing a patient
- Confirmation faxes to ACS and the investigative site
- Management of warehouse and site drug inventory in "just-in-time" fashion
- Drug expiration tracking
- A secure and tested backup and disaster recovery plan
- A system validated by standards that meet the FDA requirements based on
"Guidelines on General Principles of Process Validation" and the Device
Manufacturing Practices Parts 211.68 and 820.61
- Support in at least 21 languages that is available 7 days a week, 24
hours a day
Appendix 1 contains detailed summaries and specifications for each of the
above items.
SITE INITIATION, MONITORING, AND MANAGEMENT
ORGANIZATION AND CONDUCT OF THREE INVESTIGATORS' MEETINGS
Covance will organize and conduct three Investigators' Meeting tentatively
scheduled for October 1998 and January 1999. The North American meeting
will be held in Irvine, California. The European meeting will be conducted
in Brussels, Belgium. The Brazilian meeting location is yet to be
determined.
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ACS and Covance will work together to develop the agenda and presentation
responsibilities for each meeting and will conduct a rehearsal meeting
prior to the first Investigators' Meeting. Each meeting is expected to be
one day in length. To ensure consistency in meeting presentations the
Covance International Project Director will attend each meeting. The
following attendees are anticipated to attend the meetings:
- Principal investigator from each site
- Study coordinator from each site (North America only)
- Five ACS project team members per meeting (only 2 assumed for Brazil
Meeting)
- Twelve Covance project team members for the North American meeting
- Nine Covance project team members for the European meeting
- Three Covance project team members for the Brazil meeting
INITIATION VISITS
Covance will be responsible for study initiation visits pending ACS's
approval of the investigator's regulatory documents and after shipment of
study drug has been approved. Covance has assumed Covance will conduct 128
site initiation visits for this program. In addition, the German contract
CRA will conduct 17 visits. Each initiation/monitoring visit will require
approximately 14 hours spent on site. An additional six hours are allotted
for preparation, travel, and report generation. At each initial visit, the
Covance monitor will be responsible for reviewing with the investigator
and site staff the protocol, the CRF and procedures for its completion,
regulatory documentation and requirements, the details of drug dispensing,
storage, and accountability, serious adverse events reporting and
requirements, and other administrative aspects of the program.
Covance will provide a monitor's report to ACS electronically (via
Covance's Trial Tracker System) within ten working days of completing an
initiation visit. Covance will define the format of the initiation visit
reports.
ROUTINE MONITORING VISITS
Following the initial initiation/monitoring visit, Covance will conduct
monitoring visits approximately every six to eight weeks during the
enrollment period and every 12 weeks thereafter for the duration of the
program. Each routine monitoring visit will last 16 hours including time
for preparation, travel, and report generation. ACS may elect to
co-monitor some of the visits with the Covance monitor. Covance also has
assumed that ACS has identified and contracted with a contract CRA in
Germany who will monitor all active sites in Germany. Table 6 displays the
number of monitoring days by study Covance has
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assumed in this proposal. Covance has assumed 20 of the North
American sites will be non-productive and not require
monitoring visits. Prior to determining a site is
non-productive, Covance suggests conducting a follow-up
training site visit for inactive sites. Costs for this visit
are not included.
TABLE 6
MONITORING DAYS BY LOCATION
-------------------------------------------------------------
LOCATION MONITORING DAYS
-------------------------------------------------------------
North America Study 1,393
European Study (includes Brazil)* 972
-------------------------------------------------------------
* Assumes ACS contract CRA will monitor all German sites
Covance proposes to decouple retrieval of CRFs from monitoring
visits for this program. This strategy will allow
investigative sites to submit patient CRFs as soon as possible
following a patient visit. This will allow Covance to enter
data into the clinical database as early as possible. The
monitor will review the patient's source documentation against
the site's copy of the CRF. Any corrections or additions to
the CRF will be noted on a Data Clarification Form, which will
be signed-off by the investigator and forwarded to Covance's
data management group for processing.
Covance monitors will ensure that information collected in the
CRF is complete and accurately reflects the information
recorded on the patient's medical chart. During monitoring
visits, Covance monitors will review the following:
- Appropriate patient enrollment and randomization
- Protocol and patient compliance
- 100% of the CRF data fields for accuracy, completeness, and
consistency with source documentation
- Investigator's Study File Notebook (e.g., study logs, signed
patient informed consents forms, etc.)
- Drug supplies, pharmacy records, and appropriate drug
storage
- Data received regarding the safety of the drug
- Regulatory compliance (IRB/IEC correspondence, etc.)
- Appropriate review of other data instruments for
completeness, accuracy, and consistency with source
documents
Covance will provide a monitor's report to ACS electronically
(via Covance's Trial Tracker System) within ten working days
of completing a monitoring visit that will define any issues
found or discussed at the site. Covance will define the format
of the monitoring reports.
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CLOSE-OUT VISITS
Where possible, Covance will close sites at the time of the final
monitoring visit. Covance has assumed that non-accruing/non-productive
sites will require a separate site visit for close-out. Each close-out
visit will last ten hours including time for preparation, travel, and
report generation.
Covance will ensure that all site documentation is complete and accessible
for potential future FDA or other regulatory authority audits, that the
investigator is aware of his or her continuing responsibilities, and that
all remaining clinical trial materials to be returned to ACS are removed
from the investigative site.
Covance will provide a monitor's report to ACS electronically (via
Covance's Trial Tracker System) within ten working days of completing a
close-out visit.
IN-HOUSE SITE MANAGEMENT
Between monitoring visits, Covance will maintain weekly telephone contact
with investigative sites to discuss patient accrual, adverse experiences,
query resolution, and any other study related issues. Covance will provide
written documentation to ACS of all critical issues discussed.
QUALITY ASSURANCE SITE AUDITS
Quality Assurance Good Clinical Practices site audits will be conducted by
Covance's Quality Assurance personnel. ACS has requested that 10% of sites
will undergo a Quality Assurance Audit. Therefore, Covance will conduct
eight site audits in North America, one site audit in Brazil, and six site
audits in Europe for this program. Covance will provide audit reports to
ACS within four weeks of conducting an audit. Covance has assumed that each
audit will require three days on site to complete.
SERIOUS ADVERSE EVENT REPORTING
SERIOUS ADVERSE EVENT REPORTING PLAN
Covance and ACS will work together to develop a serious adverse events
(SAE) reporting plan. The plan will define procedures and responsibilities
for collecting, reporting and tracking SAEs. ACS will provide final
approval and sign-off of the plan.
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SAE REPORTING
ACS has asked Covance to assume 80 SAEs per study (160 total)
with one follow-up report per event on average. Covance will
use its standard SAE report forms. Covance will collect and
forward all SAE information from the investigators to ACS
within 24 hours of receipt. Covance also will collect SAE
follow-up information and forward the information to ACS.
Information on events occurring in North America will be
collected by Covance's Walnut Creek office. Information on
events occurring in Europe will be collected by Covance's
Maidenhead, UK office. Information on events occurring in
Brazil will be collected in Covance's Buenos Aires, Argentina
office. In processing SAEs, Covance will be responsible for:
- Providing medical evaluation
- Writing all SAE narratives
- Submission to ACS for filing with the FDA and HPB
- Reporting and submission of all reportable events in
compliance with applicable local regulations in Europe and
Brazil
- Notifying investigators of any events per local regulations
ACS will determine whether each SAE requires submission to the
FDA and submitting reportable SAEs to the FDA and HPB. Covance
has assumed 20% of SAEs (total of 32) will be reported to the
Regulatory Agencies.
SAE DATABASE
Covance will establish and maintain an SAE database and will
be responsible for reconciling the SAE and clinical databases.
PROJECT MANAGEMENT
OVERALL PROJECT MANAGEMENT
Covance has assigned ▇▇▇▇▇▇ ▇▇▇▇▇▇▇▇▇ as the International
Project Director and ▇▇▇▇▇▇▇ ▇▇▇▇▇▇, Christiane Booremans, and
▇▇▇▇▇ ▇▇▇▇▇▇▇▇ ▇▇▇▇▇▇ ▇▇▇▇▇ as regional Project Managers in
the United States, Europe, and Brazil, respectively.
The International Project Director will be responsible for:
- Leading the Covance Vitrase(TM) project team and providing
expertise as needed
- Serving as ACS's key point of contact within Covance
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- Maintaining effective communication with ACS and all groups performing
project work
- Preparing of project plans, timelines, and milestones
- Directing all activities required to meet Covance's obligations to ACS
- Ensuring Covance's budgetary, on-time, and quality performance
The regional Project Managers will serve under the International Project
Director and be responsible for coordinating the daily activities of the core
and extended Covance project team. The Project Managers will report directly to
the International Project Director on project status and issues.
COMMUNICATION WITH ACS
The Covance International Project Director will maintain contact with the ACS
Clinical Operations representative throughout the program. Covance has assumed
core project team telephone conferences will be conducted weekly and that
face-to-face meetings between ACS and Covance will occur quarterly with
Covance's North American team throughout the program. Covance's European Project
Manager will attend project team teleconferences on an as needed basis and
face-to-face meetings annually. Covance and ACS will conduct a contract and
budget status review in coordination with the quarterly face-to-face team
meetings. Covance has assumed these meetings will alternate between ACS's and
Covance's offices. A minimum of four Covance project team members will attend
each meeting.
PROJECT STATUS REPORTING
It is Covance's intention to provide ACS with project status reporting through
Covance's Trial Tracker system, which will allow ACS 24-hour access to key
project status information. ACS's project team members will be able to access
Trial Tracker from their desktops via Covance's network. A technical support
individual based in Covance's Walnut Creek office will be available on an
"on-call" basis to address any Trial Tracker issues. For each study, Trial
Tracker will contain modules that will provide the following information to ACS:
- Investigator data
- Names and addresses
- Budget/Payment Status
- Regulatory document status
- Monitor's trip reports
- Pre-study investigative site visits
- Initiation investigative site visits
- Monitoring investigative site visits
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o Close-out investigative site visits
o Patient enrollment data
o Site contacts
o Telephone contacts
o Protocol exceptions
o Common study site issues
o CRF retrieval and correction tracking data
o SAE summaries
Appendix 2 provides details on each of the Trial Tracker modules.
Covance will update Trial Tracker information on a daily basis. The
timeliness of the information contained within the individual modules will
depend on the nature of the data collected for the specific module. For
example, monitoring visit trip reports are scheduled for delivery to ACS
within ten days of completion of the site visit. Therefore, information
entered into the Site Visit Report Module will pertain to visits that
occurred up to ten days before the daily system update.
MAINTENANCE OF STUDY MASTER FILES
In accordance with the International Conference on Harmonization (ICH) Good
Clinical Practices and local applicable regulations, Covance will maintain
study files that consist of the original CRFs, investigator regulatory
documentation, and correspondence between ACS and the investigative sites.
Covance will maintain the study files until completion of the program
unless ACS requests provision of the files prior to completion of the
program, at which time they will be forwarded to ACS. ACS will have access
to the study files at all times.
DATA MANAGEMENT
DATA MANAGEMENT PLAN
Data Management activities for both studies will be conducted out of
Covance's Walnut Creek office.
Covance will be responsible for developing a Data Management Plan for this
program. Covance will provide a draft of the Data Management Plan to ACS
for review and comment.
The Data Management Plan will include, but not be limited to:
o Definition of a data segment
o CRF log-in, pre-data entry clarification, and data entry procedures
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- Coding specifications
- Data coordination procedures (i.e., review systems, validation of data,
query generation and resolution, and database correction procedures)
- Database audit procedures
DATABASE DESIGN
Covance will develop separate but identical CRF database structures for
the European study (including Brazil) and for the North American Study.
CRF PROCESSING AND DATA ENTRY
CRFs will be directly submitted by the study sites to Covance's Document
Control Center in Walnut Creek as quickly as possible after the patient
visit. Once in house, data personnel will inventory and forward the CRFs
for data entry. Covance's CRF tracking system will track the CRFs
throughout the data entry and data management process. Working copies of
the CRF will be stored in Covance's Document Control Center and the
original white copies will be kept in a separate off-site storage facility.
Entry of the data from each CRF will occur promptly to ensure a current
database. Data entry will be performed on an on-going basis by two
independent operators: the first operator performs the initial entry and
the second operator performs second key verification of all numeric and
date fields, adverse experiences, and concomitant medications. Lengthy
text fields (in excess of 80 characters) will be entered by the first data
processor, then sight verified by the second operator. Any questionable
discrepancies will be addressed by a Data Manager. Covance will data enter
up to 57,600 CRF pages (1,600 patients x 36 CRF pages).
DATA REVIEW AND CLEAN-UP
The data review process will begin with the preparation of Data Review
Guidelines, which will specify the computerized validation checks and query
conventions. The Data Review Guidelines will be developed when the CRF
Monitoring Conventions and Site Manual are developed, thus ensuring
consistency and appropriateness in approach to data collection and
handling. ACS will review and sign-off on the Data Review Guidelines.
Data review will occur on an ongoing basis. Covance will immediately
correct and document data problems that can be resolved through intra-CRF
verification and without discussion with an investigator's staff. Data
queries that require resolution with an Investigator's staff will be
addressed by mail, facsimile or, if necessary, with investigative site
staff during the next monitoring visit. Covance's standard procedures
ensure that all corrections to a CRF are
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appropriately documented, reviewed, and approved by the investigator. Covance
will review and clean up to 57,600 CRF pages (1600 patients x 36 CRF pages).
ADVERSE EVENT AND CONCOMITANT MEDICATION CODING
Covance will be responsible for applying coding conventions to adverse events
and concomitant medications. Covance has assumed that it will use Covance's
standard COSTART dictionary to code intercurrent illnesses and adverse events
and Covance's standard WHODRUG dictionary to code concomitant medications.
Costs for additional coding for specific ophthalmologic events that cannot be
coded by COSTART have not been included in this proposal.
QUALITY CONTROL AND QUALITY ASSURANCE OF THE DATABASE
To ensure data quality, Covance will conduct a database audit (a random
sampling of the database verified with the hard copy CRF, item by item) of each
database. Covance will use its Standard Database Audit error rate of 0.05% or
less as the threshold for accepting a file. If the error rate is above 0.05%,
Covance will reject the file and conduct a systematic review of the database
for errors.
In addition, per Covance SOPs, Covance Regulatory Compliance personnel will
conduct a database audit on 10% of patients.
TRANSFER OF CLINICAL DATA
Covance will conduct one test data transfer to ACS of a populated database
using data structures compatible with ACS standards prior to CRF data entry.
Dummy data included in the test transfer will be prepared by Covance. Table 7
defines the data transfers per study.
TABLE 7
DATA TRANSFERS BY STUDY
-------------------------------------------------------------------------------
NORTH EUROPE AND
TRANSFER AMERICA BRAZIL TOTAL
-------------------------------------------------------------------------------
Dummy Data 1 1 2
IND Updates 3 3 6
Final Transfer 1 1 2
Total 5 5 10
-------------------------------------------------------------------------------
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CRF DISPOSITION AND ARCHIVAL
Covance will be responsible for coordinating the disposition of the
CRF's after the trial is completed.
STATISTICAL ANALYSIS
STATISTICAL ANALYSIS PLAN
Covance will prepare a Report and Analysis Plan (RAP) for the final
analyses for each study. Covance has assumed each RAP will be finalized
early in the program prior to data analysis and will be identical for each
study.
The RAP will define all statistical analyses and will include an outline
of the statistical report with table, listing, and figure mock-ups. ACS
will review the draft RAPs and provide comments to Covance, who will be
responsible for incorporating ACS's comments and preparing final drafts
for ACS to sign-off. Covance has assumed two review cycles for each RAP.
STATISTICAL PROGRAMMING AND ANALYSIS
Covance programmers will be responsible for creating programs for the
development of safety and efficacy tables and listings. The programs will
be based on the programs used to create the tables, listings, and figures
from the Phase II analyses. Covance has assumed a total of 100 tables,
listings, and figures for each of the 3 and 12 month final analyses.
Analyses, tables, and listings will be substantially the same for the 3
and 12 month analyses, with the exception of changes necessary to
accommodate additional timepoints at 12 months. Covance has assumed two
review cycles by ACS will be required prior to sign-off on final tables,
listings, and figures by ACS.
CLINICAL STUDY REPORT PREPARATION
CLINICAL STUDY REPORT
Covance will be responsible for preparation of the Clinical Study Reports
(CSR) for each study. Covance has assumed two CSRs per study: one after
completion of three months in the study by all patients and one after
completion of 12 months in the study by all patients. Covance will prepare
the reports using Covance's standard report format, which follows ICH
Guidelines. Covance will use the individual patient narratives from the
SAE reports in the CSRs. Covance has
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assumed that ACS will conduct two review cycles prior to sign-off on the
final CSRs.
NDA PREPARATION
NEW DRUG APPLICATION
Early in the program, ACS and Covance will meet to define organizational
responsibilities as related to the Vitrase(TM) New Drug Application (NDA).
Following that meeting Covance will provide ACS with an estimate for its
services as related to the NDA. No costs are provided within this Time and
Cost Estimate for Covance's assistance with the Vitrase(TM) NDA.
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IV. COST ESTIMATES
Table 8 presents estimated Out-of-Pocket (OOP) Costs, Table 9 presents
estimated Covance Fees, and Table 10 presents estimated OOP costs and Covance
Fees for Covance Pharmaceutical Packaging Services (CPPS). Estimated Covance
fees are based upon the resources needed to complete tasks described in the
Responsibilities and Services Section of this Time and Cost Estimate.
Subsequent changes to the timelines, organizational responsibilities, and
program assumptions listed throughout this Time and Cost Estimate may have an
impact on the costs provided.
TABLE 8
ESTIMATED OUT-OF-POCKET (OOP) COSTS
--------------------------------------------------------------------------------
TASK AMERICAS EUROPE
--------------------------------------------------------------------------------
Travel (Pre-study Site Visits) $ 84,000 $ 10,000
Travel (Initiation Visits) 85,000 22,000
Travel (Monitoring Visits) 871,000 329,000
Travel (GCP Audits) 17,000 19,000
Travel (ACS-Covance Meetings) 81,000 9,500
Travel (Project Team Meetings) 5,000 15,000
Investigators' Meetings 258,000 62,000
Case Report Form Printing 20,000 17,000
Miscellaneous (e.g., Binders) 10,000 10,000
Shipping 31,000 31,000
Brazil Regulatory 23,000
IVRS Charges 17,000 --
--------------------------------------------------------------------------------
TOTAL OUT-OF-POCKET COSTS $1,502,000 $524,500
--------------------------------------------------------------------------------
OOP costs for a secure e-mail connection have not been included
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TABLE 9
ESTIMATED COVANCE FEES PER TASK
TASK AMERICAS(a) EUROPE
---- ------------ ----------
Regulatory Submission (Brazil) $ 19,000 $ 68,000
Protocol/Case Report Form Preparation(b) 47,000 3,000
Pre-Study Preparation 390,000 135,000
Initiation Visits 170,000 99,000
Monitoring Visits 1,491,000 1,155,000
Project Management 1,416,000 329,000
Site Management 1,176,000 381,000
Data Entry 207,000 --
Data Clean-up 976,000 118,000
Biostatistical Programming and Analysis(b) 280,000 0
Clinical Study Report Preparation 219,000 0
Site Audits 54,000 33,000
Drug Supply Management (includes IVRS) 338,000 28,000
Project Support 1,154,000 276,000
----------- ----------
TOTAL COVANCE FEES $ 7,937,000 $2,625,000
----------- ----------
(a) Costs include international project management, data management,
analysis, report preparation and IVRS for both studies.
TABLE 10
ESTIMATED COVANCE PHARMACEUTICAL PACKAGING (CPPS) OOPS AND FEES
TASK BRAZIL EUROPE
---- ------ ----------
Drug Supply Management OOPs(a) 34,000
Drug Supply Management Fees 5,000 122,000
------ ----------
TOTAL CPPS OOPS AND FEES $ 156,000
==========
(a) OOPs for Brazil will be provided once the process for transporting
study drug within Brazil to the sites has been finalized. Original
estimates for a drug depot in Brazil were estimated to be
$10,000-$20,000. Covance and ACS will continue to define logistics for
drug distribution in Brazil.
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APPENDIX 1
COVANCE'S INTERACTIVE VOICE RESPONSE SYSTEM
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COVANCE'S INTERACTIVE VOICE RESPONSE SYSTEM
Covance will be responsible for randomization for ACS's Vitrase(TM) Phase
III studies. We propose the use of Interactive Voice Response System
(IVRS).
GENERAL IVRS OVERVIEW
The IVRS patient randomization system provides computerized patient
randomization using touch-tone telephone equipment and computerized voice
output. Covance's IVRSs have been in use since 1989 in over 130 protocols.
More than 52,000 patients have been randomized and over 525,000 drug
assignments have been performed in more than 32 countries using toll-free
telephone numbers. Covance's IVRS is capable of supporting at least 21
languages and is available 7 days a week, 24 hours a day.
IVRS FUNCTIONAL REQUIREMENTS
The following functions will be available:
Site access to the IVRS
With a touch-tone telephone, study staff will call the IVRS using a
toll-free number. The IVRS will prompt the caller for his or her
identification number and preassigned access code. The identification
number is a unique number that identifies the caller. The access code has
been implemented as a security measure.
Patient Randomization
Callers can randomize patients by entering specific project and patient
information. All information entered by the caller is repeated by the
system for verification prior to randomizing a patient; this allows the
caller the chance to correct mis-entries during the call. Upon
verification from the caller, the IVRS assigns the patient an
identification number and a treatment arm from the randomization scheme
generated by a Covance statistician. This will provide real-time patient
enrollment.
Drug numbers can be dynamically matched to the patients at the moment of
the randomization and drug assignment. No pre-association between patient
and drug numbers is required. This disassociation allows the ACS to start
up the trial with minimal study drug supplies.
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An additional advantage of the IVRS is that it allows ACS to have the
ability to control patient stratification, for example by age.
Randomization can be done at site level and allow for balancing of the
patient population at site or treatment level as patients are enrolled in
the study.
Confirmation Faxes
The system will automatically fax confirmation statements after each
randomization to both the study sites and ACS. These documents will serve
as written verification of the randomization for auditing purposes.
Drug Ordering and Inventory Management
The IVRS will manage the warehouse and site drug inventory in a
"just-in-time" fashion. This allows for limited initial drug supplies and
minimal drug inventory at the sites, which is achieved by using actual
patient enrollment data along with predetermined resupply algorithms. The
drug inventory algorithms account for drug at warehouse, drug in route,
drug at sites, and drug dispensed.
Drug Expiration Tracking
The Covance IVRS maintains drug lot numbers, kit numbers, expiration
dates, and batch numbers. This allows the IVRS to categorize expired drug
as unassignable within the system. In addition, if there is a drug recall
this information allows the tracking of how much drug remains and where it
is. Thus, measures can be implemented to ensure the appropriate drug
inventory.
Script Translations and Recordings
If applicable, Covance will provide translations and recordings through
our preferred vendor, which has certified language translators. Scripts in
all languages are recorded by a voice professional at a recording studio
to provide a high sound quality IVRS.
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System Architecture
The IVRS architecture consists of an industry standard client/server and
computer telephony components. The database server is Sybase System 11, running
in a UNIX environment. The voice server component is designed with Dialogic
voice cards, the leading computer telephony boards, and Artisoft's Visual
Voice, an industry-leading computer telephony software development kit. The
IVRS voice servers run on Windows NT, the operating system standard for
computer telephony applications.
The system architecture has been designed with redundancy to handle component
or complete system failure in the event of a disaster; voice servers have dual
power supplies, disk-mirroring, and redundant disk arrays. Each voice server
acts as a backup to the other in the event of voice server failure. The Sybase
database server also has error correcting memory, disk-mirroring, redundant
disk arrays, and a backup processing unit. The backup processing unit is linked
to the primary unit via Hewlett Packard's Servicegard software. If the primary
processing unit fails, the backup processor will replace its functionality
within minutes.
Backup and Disaster Recovery
A disaster recovery plan has been developed and tested to support the IVRS
architecture. Its purpose is to minimize interruptions to the IVRS in the event
of hardware failures and natural disasters. An alternate site is maintained in
Covance's Nashville, Tennessee office to recover IVRSs operations during these
types of events.
Switching operations to the alternate site is estimated to take less than one
hour. This involves Covance's long distance telephone carrier to redirect the
toll-free service to the alternate site, as well as Covance staff to activate
the backup database server and voice server in Nashville. In the event that
Covance temporarily recovers to its alternate site, Covance will transfer data
to ACS by diskette or other designated media until operations resume at the
Covance Princeton site.
Complete backups of all systems and data are performed on a daily basis (seven
days/week) and are maintained off-site.
System Validation
The IVRS software produced and administered by Covance is validated by
standards that meet the FDA requirements based on "Guidelines on General
Advanced Corneal Systems 20 October 1998
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53
Principles of Process Validation" and the Device Manufacturing Practices
Parts 211.68 and 820.61.
All Covance IVRSs are validated following the Covance Computer System
Validation SOP. This SOP covers types of validation testing, the test
plan, the results, and change control. The contents of the SOP are as
follows:
- The Types of Validation Testing section describes unit testing,
subsystem testing, system testing and acceptance testing.
- The Test Plan section describes the minimum test plan inclusion
requirements. These are system description, subsystem list, glossary of
terms, validation environment, test procedures, and test sheets.
- The Test Results section describes the approval signature sheet, test
sheets, source code, test data, system output, error logs, error
resolution, and other documents.
- The Change Control section describes the documentation and testing
requirements for modification of the source code to add features and fix
problems, changing any part of the operating environment software, or
any hardware used.
DATA REVIEWS
A series of data reviews are performed throughout the life of an IVRS to
ensure that a project's significant operating requirements are being met.
Typical "business rules" may include: safety issues (such as assignment of
treatment type or dose regimen); correct randomization; stratification or
balancing; uniqueness of patient and drug numbers; windows of time between
visits issues; and adherence to inclusion/exclusion criteria. These data
reviews are appropriately documented, then reviewed and approved by
validation and project management, and then become part of the permanent
validation documentation for the project's IVRS.
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STUDY ASSUMPTIONS
The following assumptions were made in preparing these estimates:
- This is a Randomization and One Time Drug Assignment IVRS.
- Options included are:
-Randomization
-Drug Assignment
-Patient Query
- A manual system will be utilized until 16 November 1998:
-Each call will take approximately 1/2 hour to process.
-Assume 2.25 patient/site will be randomized from 1 October 1998 -
16 November 1998.
-Site will call into the IVRS helpdesk and provide the required
information to the helpdesk associate (ID, password, patient
date-of-birth, gender). The helpdesk associate will provide the
patient number, treatment assignment and the color of the
instructions to prepare the medication. This information will be
obtained from paper randomization lists. A manual confirmation fax
will be sent out to the site.
- Total IVRS duration is 16 months.
- Covance will be ordering drug on a site by site basis; Covance will not be
performing drug forecasting for manufacturing purposes or projected
country level needs.
- There is only 1 drug assignment per patient.
- A touch-tone phone is required for investigators to interface with the
IVRS; if an Investigator does not have a touch-tone phone, an adapter will
be provided for a fee of $20 per adapter.
- In order to access the IVRS, toll free phone numbers will be provided;
toll-free phone service is for IVRS only.
- IVRS staff will participate in 1 in-person Client meeting (8 hours).
- 1 in-house audit visit will occur with at least two Covance partners.
- All IVRS functions will be tested and validated prior to system activation;
the validation process will be conducted in accordance with IVRS
Validation SOPs.
- Study drug expires every 12 months.
- One data transfer has been assumed.
- Express mail costs are not included.
- Covance, Inc. will provide the patient randomization codes. All
randomization schemes imported into the IVRS will be 100% verified by
Covance.
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55
COST EFFICIENCIES
Cost savings and efficiencies can be recognized by utilizing the drug management
services provided via the Covance IVRS. These savings include:
- Reduction in drug manufacturing
- Reduction in drug packaging
- Reduction in drug labeling
- Reduction in drug storage (warehouse)
- Reduction in the quantity of drug to be destroyed
- Reduction in the time to perform drug reconciliation
- Total drug inventory management real time
Clinical support will not be required to track the following study parameters
as the data can be provided from the IVRS database via Trial Tracker:
- Patient enrollment and status
- Discontinuations
- Drug expiration dates
- Clinical supplies at the site and warehouse level
- The system also allows for total control over patient enrollment (i.e.
"turning off" a site or closing enrollment once enrollment numbers are
met) and for interim analysis/trend analysis to be completed.
Your study centers benefit from these services as well;
- Eliminates the time required to manually track enrollment and the time to
communicate this information to ACS.
- Reduces the amount of storage space required for drug at the site.
PROJECT MANAGEMENT BENEFITS OF USING AN IVRS
An IVRS will allow ACS to conduct project, site and study drug activities more
efficiently by providing reports on patient enrollment and demographics,
patient visits, and drug inventories. For example, an IVRS would give ACS the
ability to know real time patient enrollment and patient status; to turn on/off
patient enrollment when target numbers are reached at site, region, country or
study level; or to add or delete treatment arms at any time during the trial.
In terms of site management activities, an IVRS will also allow ACS to
efficiently forecast when CRFs are to be completed and submitted by the site
based on patient enrollment and site visits. Therefore, ACS will be able to
quickly determine which sites should be closed due to delinquent CRF completion
or lack
Advanced Corneal Systems 20 October 1998
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56
of adequate enrollment. The IVRS can also assist in the
planning of site audits. Finally, an IVRS would give ACS to
ability to close enrollment within minutes when decisions on
safety and/or endpoints are made.
With respect to drug management, an IVRS would allow ACS to
start with minimal supplies to allow for early trial start up.
For example, ACS could only package enough drug to allow 3%
wastage versus the traditional 40% wastage. In addition, ACS
will have the ability to track expiration dates and batch
numbers; to recall and stop dispensing any particular drug
batch immediately; and to track drug inventories at all the
various depots and countries.
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APPENDIX 2
COVANCE'S TRIAL TRACKER SYSTEM
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COVANCE'S TRIAL TRACKER SYSTEM
Trial Tracker is an integrated project management tool used by Covance
teams to collect, monitor and report key study activities. The approach to
this system is modular, allowing the Covance and ACS teams to select
desired modules, as well as modify the contents of each selected module for
optimal customization for each unique project. Covance has assumed that ACS
will have access to the following modules:
TRIAL TRACKER MODULES
MODULE OBJECTIVE
Trial Tracker a central menu system, which acts as the main interface to Trial Tracker.
Menu
Investigator acts as central list of study investigator names and addresses. The
Database Investigator Database assures consistency across Trial Tracker systems by
sharing key information about study sites.
Investigator tracks the collection of study regulatory documents and identifies sites which
Recruitment are ready for initiation. Investigator Recruitment allows the team to select good
clinical sites and move them quickly through the approval process.
Grant Payments facilitates the study payment process from Project Director, through Finance,
and to the Investigator. This process allows for effective financial tracking and
timely payments.
Trip Reporting collects site pre-study, initiation, routine, and final monitoring reports created by
the Covance project team. Trip Reporting expedites the creation, review, and
approval of site monitoring reports.
Patient Tracking records each patient's current status and builds a history of each patient's visits
(projected and actual). Patient Tracking allows the Covance team to monitor
patient activity at each site and creates summary reports for the entire project.
Contact Log allows the team to record issues raised during phone contacts, track protocol
exceptions, and organize the project team list. The Contact Log identifies
issues frequently raised by sites enabling the team to take corrective action.
Sherlock Tracking displays the current status of CRFs as they are received, entered, reviewed
and cleaned by Covance. Sherlock Tracking allows the team to monitor data management
activities and identify trends in the processing of CRFs.
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APPENDIX 3
COVANCE PHARMACEUTICAL PACKAGING SERVICES ESTIMATES
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60
--------------------------------------------------------------------------------
CPPS STUDY COST ESTIMATION
--------------------------------------------------------------------------------
PROTOCOL NO.: VITRASE PROGRAMME
(ACS)
INTERNAL NO.: 400260
CONTENTS:
SECTION I - JOB SPECIFICATION/DESCRIPTION
SECTION II - QUOTE
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SECTION I
--------------------------------------------------------------------------------
JOB SPECIFICATION
--------------------------------------------------------------------------------
Advanced Corneal Systems 20 October 1998
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62
STUDY DESCRIPTION
PREPARATION AND APPLICATION, INCLUDING LANGUAGE TRANSLATION, OF A LABEL
COMPLYING WITH LOCAL LANGUAGE REGULATIONS TO READY PACKAGED MEDICATION AND THE
DISTRIBUTION OF THE MEDICATION AND ANY ADDITIONAL MATERIAL IS WHAT IS REQUIRED
FOR THIS STUDY. IF ADDITIONAL SERVICES ARE REQUIRED OR THE DETAILS WITHIN THIS
QUOTATION ALTER THEN COST WILL BE REVISED ACCORDINGLY.
THE PROGRAMME IS DUE TO RUN IN THE UNITED STATES AND EUROPE. THIS DOCUMENT ONLY
COVERS THE EUROPEAN COUNTRIES.
Assumptions of participating countries
COUNTRY NUMBER OF SITES NUMBER OF PATIENTS
-------------- --------------- ------------------
FRANCE 13 130
GERMANY 17 ▇▇▇
▇▇▇▇▇ 10 ▇▇▇
▇▇▇▇▇▇▇▇▇▇▇ 6 72
POLAND 8 88
UK 10 120
ASSUMED STUDY REQUIREMENTS
First patient enrolled in study November 1998. (Could be US).
Last patient enrolled January 2000.
Assume 1 Vitrase vial and 1 Vitrase clinical kit per patient.
Despatch requests to be provided via IVRS directly to CPPS-Horsham.
CPPS-Horsham will be provided with drug supplies that are both primary and
secondary packaged. This will be delivered from ACS. CPPS-Horsham will need to
overlabel the Vitrase vials and apply an additional label on the Vitrase
clinical kit.
CPPS-Horsham will design a label based on English text for each participating
country, ensuring that all local cGMP requirements are adhered to.
Covance will be responsible for the label language translations. This will be
co-ordinated through the Covance regulatory group, by CPPS-Horsham.
Advance Corneal Systems 20 October 1998
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63
The country specific labels will be applied in advance and an amount of drug
will be pre-allocated to the different countries.
Drug will be stored at 2-8 Degrees C.
Drug will be shipped at 2-8 Degrees C. in insulated boxes, accompanied by
frozen ice packs to the nominated sites.
Any miscellaneous materials, such as CRF's, Vitrase clinical kits will be
shipped at ambient temperatures.
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SECTION II
--------------------------------------------------------------------------------
QUOTE
--------------------------------------------------------------------------------
Advanced Corneal Systems 25 October 1998
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65
QUOTE FOR ACS -- VITRASE(TM) PROGRAMME.
STUDY SET UP L.3,000.00
LABEL DESIGN AND PRINTING OF LABELS
(ASSUMES 6 LABEL TYPES/2 LABELS PER PATIENT) L.4,750.00
including:
Design of label texts
Printing of secondary labels
QA review/approval
Regulatory review/approval
PACKAGING AND LABELLING L.6,250.00
including:
Preparation of packaging instructions
Labelling of vials and clinical kit boxes
QA review/approval
SHIPMENT COST FOR AMBIENT TEMPERATURE L. 80.00
PER SHIPMENT
including:
Design and printing of centre labels
Design and printing of shipping labels
Packaging material for (centre boxes)
Labels (centre labels)
Preparation of packaging and shipping instructions
Co-ordination of shipments with the medical centres,
and the forwarder
Preparation of shipping documents
Co-ordination of drug ordering with IVRS and the centres
Actual shipping costs excluded
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66
SHIPMENT COST (MULTIPLE OR SINGLE PATIENT SHIPMENT) L. 250.00
FOR COLD STORAGE PER SHIPMENT
including:
Placement of vial into plastic bag prior to despatch
Design and printing of centre labels
Design and printing of shipping labels
Insulated packaging material (centre boxes)
Labels (centre labels)
Preparation of packaging and shipping instructions
Co-ordination of shipments with the medical centres,
and the forwarder
Preparation of shipping documents
Co-ordination of drug ordering with IVRS and the centres
Actual shipping costs excluded
ESTIMATED ACTUAL SHIPMENT FREIGHT COSTS L.20,000.00
(This is possible for change and should only be treated as a guide)
DESIGN AND VALIDATION OF INSULATED SHIPPING CASES L. 1,500.00
including:
Dimensional sizing
Validation of temperature shelf life
INVENTORY MANAGEMENT PER MONTH L. 450.00
including:
Inventory management and follow up of medication
Packed medication (quality control: ▇▇▇.▇▇▇▇, batch no)
Follow up after stock levels as well as follow up of requests
for additional supplies
Inventory reports (monthly basis)
PROJECT MANAGEMENT PER MONTH L. 450.00
STORAGE PER BAY PER MONTH BETWEEN 2-8oC L. 90.00
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67
STORAGE PER BAY PER MONTH BETWEEN 15-30oC L.40.00
RETURNED MEDICATION TO BE AGREED
DESTRUCTION OF RETURNED STUDY MEDICATION TO BE AGREED
EUROPEAN RELEASE OF IMPORTED DRUG/PER BATCH L.500.00
(assumes paperwork exercise only)
▇▇▇▇▇▇▇ ▇▇▇▇▇▇ ▇▇▇▇▇ ▇▇▇▇▇
Customer Services Director General Manager
Date: 10/9/98
Advanced Corneal Systems 20 October 1998
Vitrase(TM) 45
68
[COVANCE LETTERHEAD]
16 October 1998
Advanced Corneal Systems Reference#: 3375ctm
▇▇▇▇▇ ▇▇▇▇▇ ▇▇▇▇▇▇▇, #▇▇▇
▇▇▇▇▇▇, ▇▇ ▇▇▇▇▇
RE: QUOTATION FOR ADVANCED CORNEAL SYSTEMS - PHASE III STUDIES FOR VITRASE -
STORAGE AND DISTRIBUTION - BRAZIL
This letter serves to confirm pricing and specifications for the above
referenced study. Pricing has been based on the information provided to date.
This quotation may be revised as more specific information becomes available.
ASSUMPTIONS
o Supplies will be provided for 125 patients.
o There will be 5 sites in Brazil.
o The vials of Vitrase will be packaged separate from the auxiliary supplies
and will be packaged as one lot for all treatment groups (open labeled).
o The vials of Vitrase will require refrigerated storage and shipment at 2 -
8 degrees Celcius.
o The auxiliary supplies will be stored and shipped in ambient temperature
conditions.
o This compound is not cytotoxic, a penicillin or cephalosporin, DEA
scheduled product or considered hazardous material.
o There will be one pallet of refrigerated product in storage and one pallet
of ambient supplies in storage.
o Each patient will receive one Vitrase vial and one kit of auxiliary
supplies.
o Initial site shipments will include supplies for 5 patients per site.
o There will be 2 shipments to each site (ambient and refrigerated).
o Covance Horsham will provide the validated insulated shippers.
o One shipment will be made from CPPS Allentown to a distribution company in
Brazil. Site shipments will be made from that distribution company.
o There will be 12 months of inventory and project management.
69
20 October 1998
Page 2
CPPS SUPPLIED COMPONENTS
Vitrase Vial Labels
Open labels to be printed at CPPS, Allentown
Quantity: 125
Vitrase Auxiliary Supply Labels
Open labels to be printed at CPPS, Allentown
Quantity: 125
Validated Insulated Shippers and Dividers
Provided by CPPS Horsham
Quantity: 25
Kool-it Bricks
Provided by CPPS Allentown
Quantity: 75
Plastic Ziplock Bags
To protect the vials from moisture during shipment
Provided by CPPS Allentown
Quantity: 50
CUSTOMER SUPPLIED COMPONENTS
Vitrase Vials
Auxiliary Supply Kits
ASSEMBLY: Secondary Labeling Operations (2 put-ups)
1. Vitrase Vials
2. Auxiliary Supply Kits
The vials of Vitrase will be overlabeled and placed into the
original storage containers.
The auxiliary supply kits will receive an additional label.
PRICE: Labeling of 125 patients' supplies @ $2,626.00.
Additional supplies will be billed @ $21.01/patient supply
(vial or auxiliary kit).
TOOLING: N/A
70
20 October 1998
Page 3
DISTRIBUTION: One shipment will be made from CPPS Allentown to the SAR
warehouse in Brazil @ $145.00.
Note: CPPS requires 48-hour lead time to process and ship
distribution requests. Emergency shipments requiring less
than 48-hours lead time will receive an upcharge of $50.00
per shipment.
Note: The costs for site distribution within Brazil are not
included in this quotation.
ESTIMATED BUDGET: Initial shipment to Brazil @ $145.00.
FREIGHT: Freight charges are not included in the above prices. Freight
will be billed at the carrier's cost. This includes freight for
paperwork and samples.
STORAGE AT CPPS ALLENTOWN: Ambient storage of patient supplies @ $50.00 per
pallet per month.
Refrigerated storage of Vitrase vials @ $100.00
per pallet per month.
ESTIMATED BUDGET: 1 pallet of ambient supplies
stored for 1 month = $50.00
1 pallet of refrigerated vials
stored for 1 month = $100.00
Note: The costs for storage in Brazil are not included in
this quotation.
RETURNED DRUG: Not necessary at this time.
STORAGE OF RETURNS: Not necessary at this time.
DESTRUCTION: CPPS does not handle the destruction of drug product. CPPS is able
to prepare returned or rejected drug product for shipment to an
approved Medical Waste Facility. However, the contract for
destruction and manifest for pick up of the product must be
arranged between the client and the chosen Medical Waste Facility.
If this service is necessary, it will be quoted at that time.
ADMINISTRATIVE CHARGES: Preparation of special reports required more than one
time per month will be billed @ $85.00 per technician
hour.
ESTIMATED BUDGET: 2 hours per month x 12 months
@ $2,040.00
SPECIAL NOTES/INSTRUCTIONS: N/A
71
20 October 1998
Page 4
TERMS: Net 60 Days
DELIVERY: F.O.B. Allentown, PA
ESTIMATED PRICING SUMMARY: CLINICAL PACKAGING $2,626.00
TOOLING N/A
DISTRIBUTION $ 145.00
FREIGHT TBD
STORAGE OF STUDY SUPPLIES $ 100.00
RETURNED DRUG ACCOUNTABILITY N/A
STORAGE OF RETURNED DRUG N/A
ADMINISTRATIVE CHARGES $2,040.00
TOTAL ESTIMATED COSTS $4,911.00
Thank you for the opportunity to quote.
Sincerely,
Covance Pharmaceutical Packaging Services Inc.
▇▇▇▇▇▇▇▇ ▇▇▇▇▇▇▇▇▇
Senior Clinical Coordinator
Copy ▇▇▇▇ ▇▇▇▇▇
I agree to the terms and conditions of this price estimate and understand that
if there are changes to the specifications listed above, a revised quotation may
be required.
X
--------------------------- -------------------------------
Customer Approval Signature Date
72
ATTACHMENT 1
ACS: HYALURONIDASE SOLUTION
PROTOCOL #VIT-02-08961X AND PROTOCOL #VIT-03-08961X
TRANSFER OF OBLIGATIONS TO COVANCE
20 OCTOBER 1998
73
Attachment 1
20 October 1998
Page 1
TRANSFER OF OBLIGATIONS TO COVANCE*
20 OCTOBER 1998
The following obligations of the Study sponsor will be transferred from ACS to
COVANCE.
1. The conduct of pre-study visits to assist ACS in the selection of
investigators qualified by training and experience.
2. Procurement of the following documents from each INVESTIGATOR to be
monitored by COVANCE:
a. A completed and signed Form FDA-1572.
b. Current curriculum vitae of the principal INVESTIGATOR and all
secondary INVESTIGATORS identified on Form FDA-1572.
c. PROTOCOL signature page signed by the principal INVESTIGATOR.
d. A copy of informed consent form to be used by the INVESTIGATOR.
e. IRB approval of the PROTOCOL and informed consent form.
f. As appropriate, IRB approval of PROTOCOL amendments and annual
reapprovals.
3. Provide all participating INVESTIGATORS with current investigators'
brochure and, as the investigation proceeds, keep each participating
INVESTIGATOR informed of new information received from ACS regarding the
DRUG.
4. In accordance with 21 CRF 312.32, COVANCE will promptly inform
INVESTIGATORS and ACS of any important safety information, including
serious adverse experiences received by COVANCE.
* Terms not defined herein are used herein as defined in the Clinical
Development Agreement; dated 20 October 1998, by and between ADVANCED
CORNEAL SYSTEMS, INC. and COVANCE, INC.
74
ATTACHMENT 2
ACS: HYALURONIDASE SOLUTION
PROTOCOL #VIT-02-08961X AND PROTOCOL #VIT-03-08961X
PAYMENT SCHEDULE
75
Final AO Payment Schedule
MILESTONE* EXPECTED DATE PAYMENT
---------- ------------- --------
1 Initial Payment Oct-98 $900,000
2 10% of Patients Enrolled (160 patients) Jan-99 800,000
3 20% of Patients Enrolled (320 patients) Feb-99 600,000
4 30% of Patients Enrolled (480 patients) Mar-99 600,000
5 40% of Patients Enrolled (640 patients) May-99 600,000
6 50% of Patients Enrolled (800 patients) Jun-99 600,000
7 60% of Patients Enrolled (960 patients) Aug-99 600,000
8 70% of Patients Enrolled (1,120 patients) Sep-99 500,000
9 80% of Patients Enrolled (1,280 patients) Nov-99 500,000
10 90% of Patients Enrolled (1,440 patients) Dec-99 500,000
11 100% of Patients Enrolled (1,600 patients) Jan-00 500,000
12 100% of Patients Complete Three months Apr-00 450,000
13 Last Three-Month CRF In-House May-00 340,000
14 Three Month Statistical Analysis Completed Jun-00 340,000
15 Three Month CSR Completed Jul-00 340,000
16 60% of Patients Complete 1 year Aug-00 340,000
17 80% of Patients Complete 1 year Nov-00 546,000
18 100% of Patients Complete 1 year Jan-01 504,000
19 Last 12-Month CRF In-House Feb-01 340,000
20 12 Month Statistical Analysis Completed Apr-01 350,000
21 12-Month CSR Completed May-01 250,000
22 Final Payment Jun-01 252,000
-----------
TOTAL $10,562,000
===========
*Covance will invoice ACS upon completion of milestones. All payments are due
within 30 days of receipt of invoice.
Page 1
76
ADVANCED CORNEAL
SYSTEMS
CHANGE ORDER #4 TO THE TIME AND COST ESTIMATE FOR
ASSISTANCE WITH THE CONDUCT OF ONE GLOBAL PHASE III
STUDY (PROTOCOL VIT-03-08961X) OF VITRASE(TM)
(HYALURONIDASE FOR OPHTHALMIC INTRAVITREAL INJECTION)
FOR CLEARANCE OF SEVERE VITREOUS HEMORRHAGE
Prepared for -
ADVANCE CORNEAL SYSTEMS, INC.
▇▇▇▇▇ ▇▇▇▇▇ ▇▇▇▇▇▇▇, ▇▇▇▇▇ ▇▇▇
▇▇▇▇▇▇, ▇▇▇▇▇▇▇▇▇▇ ▇▇▇▇▇
Prepared by -
Convance Clinical and Periapproval Services SA
▇▇▇▇▇▇ ▇▇ ▇▇▇▇▇▇▇▇▇ ▇▇▇
▇▇▇▇ ▇▇▇▇▇▇▇▇ - ▇▇▇▇▇▇▇
14 July 1999
Revised 10 September 1999
77
Time & Cost Estimate - Change Order #4
ACS - Vitrase
TABLE OF CONTENTS
I. INTRODUCTION 3
II. PROJECT SCOPE AND TIMELINES 4
PROJECT SCOPE 4
PROJECT TIMELINES 6
III. RESPONSIBILITIES AND SERVICES 7
EUROPE & BRAZIL 7
A. GENERAL ASSUMPTIONS 7
B. TASK SPECIFIC ASSUMPTIONS 9
C. COST ESTIMATES 16
D. CHANGE ORDER FORMS 18
E. VALIDITY 18
ATTACHMENTS
COVANCE PHARMACEUTICAL PACKAGING SERVICES 19
78
Time & Cost Estimate - Change Order #4
ACS - Vitrase
I. INTRODUCTION
On 20 October 1998, Covance Inc. (Covance) provided Advanced Corneal
Systems, Inc. (ACS) with a Time and Cost Estimate (TCE) for assistance in
conducting two Phase III safety and efficacy studies of Vitrase(TM)
involving 1,600 patients with severe vitreous hemorrhage.
This TCE includes the task descriptions and the cost estimates for one study
(protocol VIT-03-08961X) as from 1 June 1999, in response to the changes
required in the revised protocol, dated 5 March 1999. In agreement with ACS,
all expenses incurred from the start of the study until 31 May 1999 will be
invoiced to ACS on a cost incurred basis. The following list indicates the
changes affecting the scope of this program.
o VIT-02-08961X
This is a North American study. All work (with the exception of IVRS) has
been withdrawn from Covance Inc. as of 8 May 1999. IVRS work on this study
will be the subject of a separate Time & Cost Estimate (TCE).
o VIT-03-08961X
Covance will continue to work on this global study in the participating
European and Brazilian countries. Changes include:
o Deletion of watchful waiting arm
o Replacement of 7.5 IU treatment arm with saline injection arm
o Decrease in number of patients from 660 to 306
- 278 complete evaluable patients
- 28 non-completers who will be replaced
3
79
Time & Cost Estimate--Change Order #4
ACS - Vitrase
o Decrease in number of Covance responsible investigative sites from 48
to 32 in Europe and Brazil
- CroMedia will monitor sites in South Africa and
Australia/New-Zealand
- Staticon International will monitor sites in Germany and
Hungary
o Selection, pre-study and initiation of additional British and Polish
sites needed to replace French sites
o Increase in number of CRF pages per patient from 36 to 50
o Addition of an interim analysis (additional monitoring/query
resolution)
o Shift in start-up timelines because of delays in finalizing the study
protocol and delays in receiving required regulatory filing documents
required for submission to regulatory health authorities
o Brazilian Investigators' Meeting
o CroMedica will be responsible for data entry, data management and
query generation
o Covance Pharmaceutical Packaging Services (CPPS Horsham) will be
responsible for labeling of all drug supplies (including Brazil)
o CPPS Horsham will be responsible for generating randomizing envelopes
for all participating countries
o CPPS Horsham will be responsible for storage and shipment of all drug
supplies to participating countries
II. PROJECT SCOPE AND TIMELINES
A. PROJECT SCOPE
Protocol #VIT-03-08961X is a phase III, randomized, masked safety and efficacy
study of Vitrase(TM) for the treatment of severe vitreous hemorrhage, which
will be conducted at 51 investigative sites in Europe, 10 sites in South
Africa, 5 sites in Brazil, and 10-12 sites Australia/New-Zealand.
Covance is responsible for sits in The Netherlands, the United Kingdom, Poland
and Brazil.
Other countries are handled by other CROs and are not subject for this TCE.
Covance will however provide assistance for regulatory submissions in Italy and
minimal support activities for regulatory submissions in Hungary. In addition,
Covance is responsible for Investigator Package review and Serious Adverse
Events reporting to authorities for all participating countries.
4
80
Time & Cost Estimate-Change Order #4
ACS - Vitrase
All investigative sites are stand-alone sites which ACS expects to enroll a
minimum of 1.0 to 1.5 patients per month.
In Europe, South Africa, Australia/New-Zealand and Brazil, up to 561 eligible
patients will be randomized into the following three treatment arms in a 1:1:1
ratio for Protocol VIT-03-08961X.
(1) Saline Injection
(2) Vitrase(TM) 55 IU
(3) Vitrase(TM) 75 IU
While in the study, patients will be clinically evaluated at Screening and
Randomization; Days 1 and 7; and Months 1, 2, 3, 6, and 12. Patients will be
followed every six months thereafter, up to three additional years. Costs are
provided for patient monitoring and management through Month 12. Costs for
activities during the three-year follow-up period will be provided upon request
from ACS. Table 1 provides a summary of the project specifications.
TABLE 1
VITRASE(TM) PHASE III STUDY SPECIFICATIONS--PROTOCOL VIT-03-08961X
Number of Patients Enrolled 561(a)
completers 510
patients replaced (10%) 51
original --
Number of Initiated Sites 78(b)
Case Report Form Size 50 pages per patient
Enrollment Rate(c) Approximately 1.0 to 1.5 patients per
site per month
Enrollment Period(c) 7 months
Final Deliverable(d) Clean CRF
(a) ACS assumes European sites will enroll 231 patients and Brazilian
sites 75 patients
(b) Covance will initiate 27 sites in Europe and 5 sites in Brazil
(c) Enrollment rate and period projected by ACS
(d) An interim analysis will be conducted after 150 patients complete
three months.
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B. PROJECT TIMELINES
Table 2 presents the assumed timelines for the Vitrase(TM) Phase III program.
TABLE 2
ESTIMATED TIMELINES(a) - PROTOCOL VIT-03-08961X
MILESTONE DATES
--------- -----
Final Protocol (Amendment 3) 5 March 1999
Study Drug Available 1 May 1999/July 1999(b)
Site Initiations (start-end) 26 May 1999 - 30 September 1999
First Patient Enrolled 1 June 1999
Interim Analysis(c) October 1999
Last Patient Enrolled(d) 15 January 2000
Last Patient Out (3 months) 15 April 2000
Delivery of Draft 3 Month Clinical Study Reports July 2000
Last Patient Out (1 Year Follow-up) 15 January 2001
Delivery of Draft 12 month Clinical Study Reports April 2001
(a) Timeline provided by ACS
(b) Second batch to be supplied by ACS
(c) Time of interim analyses based on enrollment rate of 1.5 per patients per
month
(d) Timeline based on by ACS assumed recruitment of 1.5 patients/site/month
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III. RESPONSIBILITIES AND SERVICES
PROTOCOL VIT-03-08961X (EUROPE & BRAZIL)
Below is an outline of Covance responsibilities from 1 June 1999 through
completion of activities per the timelines stated in Section II (page 6) of this
Change Order.
A. GENERAL ASSUMPTIONS
1. THE ESTIMATES HAVE BEEN BASED ON THE PROTOCOL STATED BELOW:
STATUS
ACS PROTOCOL # NAME PHASE INDICATION (DRAFT/FINAL) DATE
-------------- ---- ----- ---------- ------------- -------------
VIT-03-08961X VVHS III Vitreous FINAL 05 March 1999
hemorrhage
2. THE TOTAL NUMBER OF PATIENTS AND SITES:
TOTAL NUMBER OF PATIENTS TOTAL NUMBER OF SITES
------------------------ ---------------------
306 32
3. END POINT OF COVANCE INVOLVEMENT IN THE STUDY IS: CLEAN CRF
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4. THE STUDY IS TO BE CONDUCTED IN THE FOLLOWING COUNTRIES:
COUNTRY # SITES # PATIENTS
------- ------- ----------
THE Netherlands 4 ▇▇
▇▇▇▇▇▇ ▇▇ ▇▇▇
▇▇▇▇▇▇ ▇▇▇▇▇▇▇ 13 56
Brazil 5 75
TOTAL 32 306
5. THE PROJECT WILL BE CONDUCTED ACCORDING TO THE FOLLOWING TIMELINES:
EVENT TIMELINE
----- --------
Agreement reached 1 March 1999
Final Protocol 5 March 1999
Study Drug Available 1 May 1999/ July 1999*
Site Initiations (start-end) 26 May 1999 - 30 September 1999
First Patient In 1 June 1999
First Patient Out 1 June 2000
First CRF to Data Management CroMedica September 1999
Last Patient In 15 January 2000
Last Patient Out 15 January 2001
Start Audits September 1999
Last CRF to Data Management CroMedica February 2001
Last Query Resolved End February 2001 **
Statistical Analysis Provided N/A
Clinical Trial Report Provided N/A
Transfer of all archive materials to ACS March 2001
* Availability of second batch to be used for supplies in Hungary, Australia
and Brazil.
** Assumes one week turnaround time of queries by outside data management group.
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B. TASK-SPECIFIC ASSUMPTIONS
All tasks required as of 1 June 1999 for the successful completion of the
Covance portion of the study are listed below with the agreed assignment of
responsibilities for each of the tasks. The cost estimates are based on the
assumptions detailed for each of the tasks.
ACS COVANCE
--- -------
A. REGULATORY SUBMISSIONS
1. PREPARATION OF CLINICAL TRIAL APPLICATION
o the Netherlands Completed
o Poland Completed
o United Kingdom Completed
o Brazil X
o Italy (support for ACS consultant) X
o Hungary (minimal support) X
o Australia/New Zealand (minimal support) Completed
* Assumes no updates to the authorities.
2. REPORTING OF SAES TO REGULATORY AUTHORITIES
* Covance will report SAEs from all sites, including
non-Covance countries, i.e. Germany, Hungary,
Australia/New Zealand and South Africa. X
* Standard Covance SAE reporting forms will be used.
* Assumes a total of 17 reportable SAEs.
3. NOTIFYING INVESTIGATORS OF SAEs
* Includes notification to investigators and ethic
committees for Covance countries and to other CROs
for Germany, Hungary, Rep. of South Africa,
Australia/New Zealand. X
* Assumes a total of 17 reportable SAEs.
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B. PROTOCOL AND CRF PREPARATION ACS COVANCE
--- -------
1. PROTOCOL DESIGN Completed
* Assumes no further protocol amendments
2. CRF DESIGN Completed
3. CRF PRINTING (3-part NCR paper) Completed
4. SHIPPING OF CRFs TO INVESTIGATORS X
C. PRE-STUDY PREPARATION
1. IDENTIFY POTENTIAL INVESTIGATORS (X) (X)
* Includes 20 calls to potential new investigators.
2. MAILING PROTOCOL PACKAGES to potential investigators X
3. PRE-STUDY SITE VISITS
* Includes a total of 5 Pre-Study Site Visits. X
4. INVESTIGATOR GRANT NEGOTIATION (X) (X)
5. NEGOTIATIONS WITH SUBCONTRACTORS N/A
6. INVESTIGATORS' MEETINGS
* Includes 1 Investigators' Meeting in Brazil with 2 Covance X
attendees.
* Includes organization and attendance of the meeting.
7. FORMS DEVELOPMENT
(trip reports, investigator files, study file notebook, enrollment Minimal
tracking,....) review
8. PROJECT-SPECIFIC TRAINING
* Assumes training for 3 Covance staff members (Project X
Manager and 2 monitors).
9. TRANSLATIONS
* informed consent forms Completed
* drug reconstitution sheets Completed
* source data work sheets, to be translated into X
Portuguese (Brazil).
* Assumes no site specific changes.
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C. PRE-STUDY PREPARATION ACS COVANCE
--- ---------
10. BACK-TRANSLATIONS INTO ENGLISH Completed
* informed consent form
11. DESIGN OF MONITORING CONVENTIONS MANUAL X Revision
* Assumes no update during course of study.
12. ASSISTING INVESTIGATORS WITH ETHICS COMMITTEES X
13. DESIGN OF SAE REPORTING PLAN X
14. REVIEW OF INVESTIGATOR DOCUMENTS X
15. DESIGN OF SOURCE DATA VERIFICATION PLAN X Revision
16. UPDATE TRIAL TRACKER DATABASE to cover amendment X
17. SET-UP OF 24-HOUR MEDICAL COVER PLAN X
D. STUDY INITIATION VISITS
1. STUDY INITIATION VISITS X
* Includes a total of 31 study initiation visits.
E. ROUTINE MONITORING VISITS
1. ROUTINE MONITORING VISITS (INCL. CLOSE-OUT VISITS)
* During enrollment, visits will be performed every 4 weeks
in Poland and Brazil, and every 6 weeks in The Netherlands
and United Kingdom, plus 1 extra visit after inclusion of the
first patient and 1 visit for interim analysis. X
After the enrollment period, visits will be performed every
12 weeks for all sites.
* Includes 2 extra visits per site for unmasked monitor.
-> Total # of Routine Monitoring Visits: 489
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F. PROJECT MANAGEMENT ACS CONVANCE
1. PROJECT PLAN Revision
2. KICK-OFF MEETING Completed
3. REVIEW AND APPROVAL OF INVOICES X
4. DEVELOPMENT/MAINTENANCE OF PROJECT DATABASES Revision
5. PREPARATION OF MONTHLY STATUS REPORTS X
6. MEETINGS WITH ACS
* Includes a total of 1 face-to-face meeting per year of 1 day
duration between ACS and Covance. X
* Includes 2 Convance participants at each meeting.
7. TELEPHONE CONTACTS WITH ACS X
8. OVERALL PROJECT SUPERVISION X
9. PROJECT TEAM MEETINGS
* Includes a total of 2 meetings of 1 day duration per full
year (i.e. 1 meeting in 1999, 2 meetings in 2000 and X
1 meeting in 2001).
* Includes 7 Covance participants per meeting.
10. PROJECT FILES X
11. INTERACTION WITH OTHER CROS X
12. ARCHIVING OF CRFS and all other study documentation after
study completion X
14. SHIPPING OF CRFS and all other study documentation to ACS
after study completion X
15. PERIODIC BUDGET AND CONTRACT REVIEW, telephone calls and
meetings with ACS regarding contract issues X
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G. SITE MANAGEMENT ACS COVANCE
--- -------
1. SERIOUS ADVERSE EVENT REPORTING
- to ACS
- to data management (CroMedica)
- to authorities \
- to investigators Reportable SAEs only X
- to other monitoring CROs /
* Assumes a total of 56 SAEs.
2. MAINTENANCE OF SAE DATABASE X
3. TELEPHONE MONITORING OF SITES X
4. IN-HOUSE FOLLOW-UP OF MONITORING VISITS X
5. IN-HOUSE FOLLOW-UP OF ISSUES FOUND DURING AUDITS X
6. INVESTIGATOR FILES X
7. ADMINISTRATION OF PAYMENTS for
- Investigators (assumes a max. of 4 payments per site) X
- Patient travel, Ethic Committees, Authorities (MoH),
pharmacy fees, etc. X
8. SHIPPING OF NON-DRUG SUPPLIES TO INVESTIGATIONAL SITES
- Case Report Forms
- Pharmacy binders X
- Other
9. ORGANIZATION OF ETDRS MATERIALS TO SITES X X
10. NEWSLETTERS X
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H. DATA CLEAN-UP ACS COVANCE
-- ------------- --- -------
1. IN-HOUSE CRF REVIEW
- Includes CRF tracking, translations of investigator
comments. X
- Assumes no copying of CRFs
2. CLINICAL QUERY RESOLUTION X
3. SUPPORT TO DATA MANAGEMENT AT CROMEDICA for
reconciliation of safety data and clinical databases X
I. STATISTICAL/CLINICAL REPORTS ACS COVANCE
-- ----------------------------- --- -------
1. STATISTICAL ANALYSIS/REPORT
- Design Statistical Analysis Plan
- Statistical Analysis X
- Statistical Report
2. CLINICAL TRIAL REPORT (CTR)
- Design CTR Plan
- Production CTR X
- Review CTR
J. SITE AUDITS ACS COVANCE
-- ----------- --- -------
1. SITE AUDITS BY THE CLIENT (represented by CroMedica) with
Covance assistance
- Includes scheduling, travel, in-house file review, pre-
and post-audit discussions, assistance of the monitor X (X)
during the audit
- Assumes 9 site audits.
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ACS COVANCE
--------- -----------
K. DRUG SUPPLIES MANAGEMENT
1. SET-UP
- includes design of Drug Supply Plan, obtaining
investigator consignees, set-up tracking system X
2. DRUG IMPORTATION X
3. DESIGN OF CORE LABEL Completed
4. REVIEW OF LABELS X
5. TRANSLATIONS OF LABELS Completed
6. TRACKING OF DRUG SUPPLIES BY MONITORS for Covance
sites only X
- Under refrigerated storage conditions
- Includes re-supply requests for sites
7. WAREHOUSE STORAGE AND TRACKING OF DRUG SUPPLIES FOR ALL
STUDY SITES
- will be performed by CPPS
8. PREPARATION OF DRUG RANDOMIZATION PLAN AND BLINDING
ENVELOPES Completed
9. DISTRIBUTION OF BLINDING ENVELOPES TO INVESTIGATIONAL
SITES X
- will be performed by CPPS
10. DRUG LABELING X
- will be performed by CPPS
11. DRUG PACKAGING X
- will be performed by CPPS
12. SHIPPING OF DRUG SUPPLIES TO INVESTIGATIONAL SITES X
- will be performed by CPPS
13. REMAINING DRUG DISPOSAL X
- assumes return of drug to CPPS/destruction by CPPS
following approval by ACS
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C. COST ESTIMATES
COVANCE PROFESSIONAL FEES
Covance costs have been calculated based on staff time needed to complete all
the tasks as outlined in Section B of this proposal. Individuals from various
departments throughout Covance will participate. These individuals will be
integrated into a dedicated project team. Estimated Covance professional fees
are presented in the table below. The cost table includes the estimates as of 1
June 1999 until completion of the study. In agreement with ACS, all expenses
incurred from the start of the study until 31 May 1999 will be invoiced to ACS
on a cost incurred basis. From 1 June 1999, this contract will become a fixed
price contract.
COVANCE FEES
TASK FEES (US$)
---- ----------
Regulatory Submissions 26,900
Protocol and CRF Preparation Completed
Pre-Study Preparation 116,500
Study Initiation Visits 39,900
Routine Monitoring Visits 718,000
Project Management 525,500
Site Management 380,000
Data Entry and/or Import N/A
Data Clean-Up 75,000
Generation and Review of Tables/Listings/Figures N/A
Statistical Analysis/Statistical Report N/A
Clinical Trial Report (CTR) N/A
Site Audits 9,500
Drug Supplies Management 32,500
exclusive CPPS Horsham fees (see Attachment 1)
Project Specific Support 122,100
TOTAL 2,045,900
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OUT-OF-POCKET COSTS
Presented below are out-of-pocket costs for travel and accomodation, and
shipping of study materials to the investigational sites. These are all
pass-through costs.
OUT-OF-POCKET COSTS
ITEM COST (US$)
---- ----------
Travel and Accomodation 423,200
Client Meeting 12,300
Project Specific Training 0
Project Team Meetings 23,500
Kick-Off Meeting 0
Shipping of non-drug supplies 32,000
Printing 4,000
Patient travel t.b.d.
Investigators' Meeting, including investigators' t.b.d.
travel & accommodation
Ethic Committees' fees
Authorities' fees t.b.d.
Pharmacy fees
Custom clearance fees t.b.d.
TOTAL (EXCL. T.B.D.) 491,000
In addition to the above, the estimated fees for regulatory submissions in
Brazil are approximately $35,000. This has not been included in this TCE.
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D. CHANGE ORDER FORMS
Covance professional fees are fixed, and are based on assumptions and
specifications described in this proposal. Deviations from the assumptions and
specifications will be jointly reviewed and assessed by ACS and Covance with
regard to impact on cost and timelines. Deviations outside Covance's control or
changes in the assumptions, specifications or scope of the project resulting in
a change in time or costs will need to be re-negotiated with ACS. Once a
deviation is identified, a "Change Order Form" will be prepared by Covance, with
an estimate of the new timelines, fees and expenses associated with this
deviation. Upon ACS's approval of Covance's estimate, said change notice will be
effective. Any events or changes of assumptions which affect the time or costs
and which are within Covance's control will be the responsibility of Covance and
will not affect the program budget.
E. VALIDITY
This Time and Cost Estimate is valid for 90 days.
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ATTACHMENT
COVANCE PHARMACEUTICAL PACKAGING SERVICES
(CPPS HORSHAM)
JOB SPECIFICATION
o STUDY DESCRIPTION
Additional countries are now set to participate in this study. Therefore
packaged supplies are required for Hungary and Australia, neither of these
countries were listed among the original participating sites.
Additionally, packaging has had to be split over two runs, which was not
originally intended, as drug material was not available to pack under one
packaging campaign. Therefore packaging for original countries has to be
repeated.
Preparation and application of a label complying with local language regulations
to ready packaged medication and the distribution of the medication and any
additional material is what is required for this study. If additional services
are required or the details within this quotation alter then cost will be
revised accordingly.
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o MODIFICATION REQUIREMENTS
Items covered within this change order are as follows:
Labeling of Vitrase vials and Clinical kit cartons (including provision in each
carton of a lose two-part Saline vial label), for the following countries:
COUNTRY # VITRASE VIALS TO LABEL # CLINICAL KITS TO LABEL
------- ------------------------ ------------------------
▇▇▇▇▇▇▇▇▇▇▇ ▇ ▇▇
▇▇▇▇▇▇ 36 54
UK 28 42
Germany 32 48
South Africa 32 48
▇▇▇▇▇▇▇ ▇▇ ▇▇▇
▇▇▇▇▇▇▇▇▇ ▇▇ ▇▇▇
▇▇▇▇▇▇ ▇▇ ▇▇
QUOTE
TASK DESCRIPTION COST (US$)
---------------- ----------
LABEL DESIGN AND PRINTING OF LABELS (3 labels per
patient and setting of new texts), including design of 4,780
label texts, printing of secondary labels for
medication vials, clinical kits and saline vials,
QA review/approval, regulatory review/approval
PACKAGING AND LABELING (of material listed above),
including preparation of packaging instructions, 6,070
labeling of vials and clinical kit boxes, QA
review/approval
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TASK DESCRIPTION COST (US$)
SHIPMENT COST FOR AMBIENT TEMPERATURE - per shipment,
including design and printing of center labels, design and 130
printing of shipping labels, packaging material (center
boxes), labels (center labels), preparation of packaging and
shipping instructions, co-ordination of shipments with the
medical centers, and the forwarder, preparation of shipping
documents, co-ordination of drug ordering with IVRS and
the centers
Actual shipping costs excluded
SHIPMENT COST (MULTIPLE OR SINGLE PATIENT SHIPMENT) FOR
COLD STORAGE - per shipment, including placement of vial 410
into plastic bag prior to dispatch, design and printing of
center labels, design and printing of shipping labels,
insulated packaging material (center boxes), labels (center
labels), preparation of packaging and shipping instructions,
co-ordination of shipments with the medical centers, and the
forwarder, preparation of shipping documents, co-ordination
of drug ordering with IVRS and the centers
Actual shipping costs excluded
INVENTORY MANAGEMENT PER MONTH, including inventory
management and follow up of medication, packed 730
medication (quality control: expiry date, batch number),
follow up after stock levels as well as follow up of requests
for additional supplies, inventory reports (monthly basis)
PROJECT MANAGEMENT PER MONTH 730
STORAGE PER BAY PER MONTH BETWEEN 2-8 degrees C 150
STORAGE PER BAY PER MONTH BETWEEN 15-30 degrees C 65
RETURNED MEDICATION To be agreed
DESTRUCTION OF RETURNED STUDY MEDICATION To be agreed
EUROPEAN RELEASE OF IMPORTED DRUG/PER BATCH (assumes 810
paperwork exercise only)
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