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EXHIBIT 10.22
SUPPLY AGREEMENT
BETWEEN
CIMA LABS INC.
AND
AMERICAN HOME PRODUCTS CORPORATION
ESI LEDERLE DIVISION
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SUPPLY AGREEMENT
THIS SUPPLY AGREEMENT is signed this 14th of January 2000
between CIMA LABS., a corporation organized and existing under the laws of the
State of with offices located at 10000 Valley View Road, Eden Prairie, Minnesota
55344-9361 (hereafter, together with its Affiliates, referred to "CIMA"), and
American Home Products Corporation (acting through its division, ESI Lederle), a
corporation organized and existing under the laws of the State of Delaware with
offices located at 130 North Radnor-Chester Road, St. Davids, Pennsylvania 19087
("ESI").
ARTICLE I
DEFINITIONS
1.1 ACTIVE INGREDIENT means ethyl 4-(8-chloro-5,6-dihydro-11 H-benzo
[5,6] cyclohepta [1,2-b] pyridin-11-ylid-ene)-1-piperidine carboxylate, known
as loratadine.
1.2 ADVERSE DRUG EXPERIENCE means the definition in the current 21 CFR
"Sections 312.32 and 314.80, as in effect from time to time.
1.3 AFFILIATE means (i) any Person which at the time of determination
is directly or indirectly controlled by any party hereto; (ii) any Person which
at the time of determination directly or indirectly controls any party hereto;
or (iii) any Person which is under the direct or indirect control of any such
Person as described in subparagraphs (i) or (ii). "Control" shall in this
Section mean ownership of greater than fifty percent (50%)
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of the voting stock or other voting interests in the Person in question. For
purposes of this Agreement, Immunex Corporation shall not be considered to be an
affiliate of ESI.
1.4 AGENCY means any governmental regulatory authority responsible for
granting approvals, including Pricing Approvals, for the sale of a Product in a
country in the Territory.
1.5 COMMERCIALLY REASONABLE EFFORTS means efforts and resources
normally used by a party for a compound or product owned by it or to which it
has rights, which is of similar market potential at a similar stage in its
product life, taking into account the competitiveness of the marketplace, the
proprietary position of the compound or product, the regulatory structure
involved, the profitability of the applicable products, and other relevant
factors. It is anticipated that the level of efforts and resources may change at
different times during the product life cycle of a compound or product.
1.6 CONTROL OR CONTROLLED in the context of intellectual property
rights means rights to intellectual property sufficient to allow a grant of
rights without any obligation to any Third Party.
1.7 DIRECT MANUFACTURING COST means (a) costs directly attributable to
manufacturing, quality assurance and quality control related to a unit of
Product (i.e., those costs which vary with production), including, but not
limited to, direct labor and benefit expenses for manufacturing, and consumable
bulk and other product materials, as determined in accordance with United
States generally accepted cost accounting practices consistently applied, plus
(b) fixed manufacturing overhead costs allocable to the product based on the
actual percentage utilization (including start-up and shut-down time) of the
capacity of the manufacturing facility, including, but not limited to, direct
benefit and labor expenses for technical services and support services,
depreciation, maintenance and repairs and insurance costs associated with such
utilization of the manufacturing facility, as determined in accordance
with Untied States generally accepted costs accounting practices consistently
applied. In no event shall charges for idle capacity or under utilized
facilities be included in Direct Manufacturing Cost.
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1.8 DEVELOPMENT AND LICENSE AGREEMENT means the Development and License
Agreement between the parties signed contemporaneously with this Agreement.
1.9 EFFECTIVE DATE means the effective date of the Development and
License Agreement.
1.10 EXTENDED TERM shall have the meaning set forth in Section 9.1.
1.11 FDA means the United States Food and Drug Administration, or any
successor thereto.
1.12 GOOD MANUFACTURING PRACTICE OR GMP means the current standards for
the manufacture of pharmaceuticals, as set forth in the United States Federal,
Food, Drug and Cosmetics Act and applicable regulations promulgated thereunder,
as amended from time to time, and such standards of good manufacturing practices
as are required by the European Union and other organizations and governmental
agencies in countries in which Product is intended to be sold, to the extent
such standards are not inconsistent with United States GMP.
1.13 INITIAL TERM shall have the meaning set forth in Section 9.1
1.14 LAUNCH DATE means the date of first commercial shipment of a
Product by ESI or its Affiliates or their respective subdistributors of Product
to Third Parties in a country of the Territory.
1.15 MAJOR COUNTRY means any of the United States, Germany, or the
United Kingdom. The foregoing countries may also collectively be referred to as
Major Countries.
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1.16 NDA means a New Drug Application, as defined in the United States
Food, Drug and Cosmetic Act, as amended, and applicable FDA rules and
regulations.
1.17 PERSON shall mean an individual, a corporation, a partnership, an
association, a trust or other entity or organization, including a government or
political subdivision or an agency thereof.
1.18 PRICING APPROVAL means any approval for price or reimbursement as
may be necessary or appropriate as a prerequisite for marketing Product in a
particular country of the Territory.
1.19 PRODUCT means rapid dissolving tablets containing 10 milligrams
Active Ingredient meeting the Specifications.
1.20 REGULATORY APPROVAL means the product license or marketing
approval necessary as a prerequisite for marketing Product in a particular
country in the Territory.
1.21 REGULATORY DOCUMENTS means all regulatory submissions, Regulatory
Approvals, and Pricing Approvals.
1.22 SPECIFICATIONS means the initial specifications for the Product as
set forth in Exhibit A hereto, as may be amended from time to time by the
parties in the course of Product development and in accordance with the
regulatory submissions and/or Regulatory Approvals, or as otherwise required by
regulatory authorities.
1.23 TECHNICAL INFORMATION means (a) techniques and data, including
ideas, inventions (including patentable inventions), practices, methods,
knowledge, know-how, trade secrets, skill, experience, documents, apparatus,
clinical and regulatory
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strategies, test data, including pharmacological, toxicological and clinical
test data, analytical and quality control data, manufacturing, patent data or
descriptions relating to Product, and (b) chemical formulations, compositions of
matter, product samples and assays relating to Product.
1.24 TERM shall have the meaning set forth in Section 9.1
1.25 TERRITORY means the world.
1.26 THIRD PARTY means any Person other than a party to this Agreement
or an Affiliate of a party to this Agreement.
ARTICLE II
SUPPLY AND MANUFACTURING
2.1 MANUFACTURING During the Term of this Agreement, CIMA shall
manufacture and supply ESI with, and ESI shall purchase from CIMA Product in
accordance with the terms specified in this Article II. Subject to Section 2.9,
ESI shall exclusively purchase all of ESI's requirements of Product from CIMA
and CIMA shall exclusively supply Product to ESI.
2.2 SUPPLY PRICE
(a) Product sold to ESI by CIMA hereunder shall be in full batch
quantities. Product shall be transferred to ESI F.O.B. CIMA's place of
manufacture.
(b) The price for Product (the Supply Price) for all countries of the
Territory shall be CIMA's Direct Manufacturing Cost, estimated to be
[***CONFIDENTIAL TREATMENT REQUESTED, PORTION OMITTED FILED SEPARATELY WITH THE
SECURITIES AND EXCHANGE
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COMMISSION.***] per tablet. CIMA agrees to use Commercially
Reasonable Efforts to minimize the Direct Manufacturing Cost of
Product. CIMA shall provide final packaging in accordance with
ESI's specifications for such packaging (such packaging
specifications to be mutually agreed upon by the parties to ensure
compatibility with CIMA's procedures and equipment) if requested by
ESI at CIMA's Direct Manufacturing Cost for such packaging.
(c) ESI may place firm orders for Product having imprinting, labeling
or packaging variants in less than full batch sizes (400,000
tablets), provided that the price for product ordered in such
variants less than full batch sizes shall be increased [***
CONFIDENTIAL TREATMENT REQUESTED, PORTION OMITTED FILED SEPARATELY
WITH THE SECURITIES AND EXCHANGE COMMISSION.***] per tablet to
reimburse CIMA for making modifications to labeling, imprinting or
packaging to accommodate such partial batch size variants.
2.3 FORECASTS
(a) Upon first ANDA submission, ESI shall provide to CIMA a non-binding
rolling three (3) year Product forecast (based on calendar years and updated at
least semi-annually) for long-term manufacturing planning purposes.
(b) During the Term of this Agreement, ESI shall provide CIMA on a
calendar basis, with a non-binding one (1) year rolling forecast, providing CIMA
with a written estimate of the quantities of Product required during the next
four (4) calendar half years. Each such quarterly estimate shall contain an
update of the immediately preceding estimate with respect to the calendar
quarters referred to in such preceding estimate.
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2.4 FIRM ORDERS
(a) ESI shall place a firm order with CIMA for Product requirements at
least six (6) months in advance of the delivery date for Product for the first
order placed for Product in any country of the Territory, or for any order for
Product which would require any modification to the labeling or packaging
thereof; otherwise ESI may place a firm order at least ninety (90) days in
advance of the delivery date for Product. A firm order is a purchase order
authorizing manufacture of the Product. Notwithstanding the foregoing, if a
modification to Product or to the Specifications (exclusive of labeling) is
required for any country in the Territory, CIMA shall have at least six (6)
months from the approval of such modification by the applicable Agency to fill
any firm order for Product placed by ESI prior to such required modification.
CIMA shall supply Product to ESI as required hereunder, provided that ESI
provides CIMA with label copy which has been agreed and approved by both parties
as required hereunder and ESI's order for Product is in accordance with the
terms and conditions of this Agreement. Such order for Product placed by ESI
shall be in accordance with the provisions of this Agreement and made pursuant
to a purchase order in a form mutually acceptable to the parties. CIMA shall
ship Product in such quantities and on the dates specified in ESI's purchase
orders.
(b) Notwithstanding the foregoing, CIMA has the right to satisfy ESI's
firm order requirements pursuant to this Article II by supplying ESI with
Product in full
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batch quantities provided that CIMA may round up or down ESI's actual order for
Product to the nearest full batch.
2.5 LIMITS ON FIRM ORDERS If a firm order made pursuant to Section 2.4
is greater than one hundred fifty percent (150%) of the one (1) year rolling
forecast received by CIMA for such ninety (90) day period, then CIMA shall use
Commercially Reasonable Efforts, but shall not be obligated, to ship that
portion of the excess over one hundred fifty percent (150%).
2.6 CANCELLATIONS OF ORDERS If ESI cancels a firm order made pursuant
to Section 2.4, then ESI shall reimburse CIMA for all costs incurred by CIMA as
a result of such cancellation of such order, including materials, labor, work in
progress, obsolete inventory disposal and overhead; but this obligation shall
not cover capital costs.
2.7 PAYMENT TERMS (a) CIMA shall provide an invoice with each delivery
of Product to ESI specifying the amount that shall be due to CIMA (the
Estimated Amount), which shall be based on CIMA's good faith estimate of Direct
Manufacturing Cost per unit of Product. Within thirty (30) days after receipt of
an invoice from CIMA, ESI shall pay to CIMA the Estimated Amount.
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(b) Within thirty (30) days of the end of each calendar half year, CIMA
shall provide to ESI a report in writing setting forth in reasonable detail the
calculation of the total payments due based on CIMA's actual Direct
Manufacturing Cost of Product (the Actual Amount), for the calendar half year
for which such payment applies.
(c) In the event the Actual Amount for Product purchased by ESI in a
calendar half year is less than the Estimated Amount for that calendar half
year, then CIMA shall pay to ESI such difference amount with CIMA's report for
that calendar half year. In the event the Actual Amount for Product purchased by
ESI in a calendar half year is greater than the Estimated Amount for that
calendar half year, then ESI shall pay to CIMA such greater amount within
fourteen (14) days of ESI's receipt of CIMA's invoice for such amount with
regard to ESI's purchases of Product in that calendar half year.
2.8 QUALITY ASSURANCE
(a) Prior to the shipment of Product to ESI, CIMA shall test
representative samples of each of the batch(es) to be shipped in accordance with
validated, approved methods of analysis defined in the Specifications. CIMA
shall provide ESI with a Certificate of Analysis for each batch of Product
shipped to ESI stating that the Product so shipped conforms to the
Specifications. The Certificate of Analysis shall be in a format agreed upon by
the parties.
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(b) CIMA shall retain production samples and batch records from each
batch of Product for the longer of (i) five (5) years after the manufacture of
each such batch of Product or (ii) the time period required under GMP. Upon
request, CIMA shall provide ESI's Quality Control Department with production
samples of Product and/or copies of completed Batch records.
(c) Master batch process documentation will be prepared and approved by
CIMA as per its normal procedures. The parties agree that deviations from master
batch process documentation may be necessary from time to time. Such deviations
shall be discussed with ESI before any proposed shipment of Product. Individual
batch process documentation shall be photocopied from the approval master and
issued for each batch as per CIMA's routine system. Original batch records will
be filed securely by CIMA. CIMA will perform all in-process control tests
demanded by the approved batch process.
(d) ESI shall have the right to test Product to verify compliance with
Specifications and applicable Regulatory Approvals and CIMA shall supply ESI
with its testing procedures. ESI may, by written notice provided to CIMA within
sixty (60) days of ESI's receipt of a shipment of Product, reject all or part of
such shipment of Product if, based upon the testing of such Product conducted
under this Section 2.8, such Product does not comply with the Specifications or
applicable Regulatory Approvals. If ESI fails to notify CIMA within such sixty
(60) day period, that it is rejecting such Product, ESI shall be deemed to have
accepted such Product.
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(e) If CIMA, after good faith consultation with ESI, disputes any
finding by ESI that Product does not comply with the Specifications or
applicable Regulatory Approvals, samples of such Product shall be forwarded to a
Third Party jointly selected by ESI and CIMA for analysis, which analysis shall
be performed in compliance with applicable regulatory requirements. The findings
of such Third Party regarding whether Product complies with the Specifications
and the applicable Regulatory Approvals shall be binding upon the parties for
purposes of this Section 2.8. The cost of such analysis by such Third Party
shall be borne by the party whose findings differed from those generated by such
Third Party.
(f) If as determined in accordance with this Section 2.8, a shipment of
Product does not conform to the Specifications or applicable Regulatory
Approvals, CIMA shall replace such shipment free of charge with a substitute
shipment which meets such Specifications and applicable Regulatory Approvals
according to the following time frame: If the Product is in inventory then
conforming Product will be shipped so as to arrive as soon as practicable. If
the Product is not in inventory, CIMA will take all reasonable steps to ensure
expeditious manufacture of conforming Product which will be shipped on the next
shipping day after completion of manufacture so as to arrive as soon as possible
thereafter. In the event that testing at ESI indicates that Product does not
conform with Specifications or applicable Regulatory Approvals: (i) ESI shall
immediately notify CIMA (ii) ESI and CIMA shall mutually agree on an
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investigation program to determine the cause of the discrepancy and the outcome
of this investigation shall be used to determine disposition of the batch; (iii)
where appropriate, given the timetable for the agreed upon investigation
program, CIMA shall take all reasonable steps to ensure expeditious manufacture
and shipment of conforming Product; and (iv) shipment of such replacement
Product shall take place the next shipping day following completion of
analytical work to demonstrate conformance with Specifications and applicable
Regulatory Approvals. Shipment shall be by the quickest agreed route. At CIMA's
expense and at ESI's sole option: the non-conforming shipment shall be (i)
returned to CIMA; or (ii) disposed of by ESI, upon final determination in
accordance with this Section 2.8 that it does not meet the Specifications or
applicable Regulatory Approvals. If the non-conformity in the Product is due to
a non-conformity of the Active Ingredient with the Specifications at the time of
its delivery to CIMA, then the Replacement Product manufactured and shipped by
CIMA under this Section 2.8 and the disposal of the non-conforming shipment
shall be at the sole cost and expense of ESI.
2.9 ESI MANUFACTURE RIGHTS DURING THE TERM
Upon ESI's written request, made at any time after first ANDA
submission, CIMA shall grant to ESI the exclusive, irrevocable, transferable
right, and shall use Commercially Reasonable Efforts to transfer to ESI the
manufacturing know-how used by CIMA that is reasonably necessary to enable ESI
to manufacture Product. If ESI exercises this right, except as provided below,
ESI shall pay CIMA (a) a [***CONFIDENTIAL TREATMENT REQUESTED, PORTION OMITTED
FILED SEPARATELY WITH THE SECURITIES AND EXCHANGE COMMISSION.***]
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technical transfer fee upon successful completion of the transfer process
(defined as manufacture of validation batches of Product meeting the
Specifications), and (b) out of pocket expenses incurred by CIMA directly
related to the technical assistance needed to facilitate the transfer process.
If ESI exercises this right due to the inability of CIMA to meet ESI firm orders
for Product, for any reason other than a condition of force majeure that lasts
less than 60 days, then ESI shall pay CIMA only out-of-pocket expenses incurred
by CIMA directly related to the technical assistance needed to facilitate the
transfer process.
2.10 NOTIFICATION OF INSPECTIONS Each party agrees to notify the other
within two (2) business days of its receipt of notification of any inquiries,
notifications, or inspection activity by any Agency, regulatory authority or
other authority in regard to or affecting Product. The recipient party shall
provide a reasonable description to the other party of any such governmental
inquiries, notifications or inspections promptly (but in no event later than
five (5) calendar days) after notification of completion of such visit or
inquiry. The recipient party shall furnish to the other party, (i) within two
(2) business days after receipt any report or correspondence issued by the
Agency or regulatory authority in connection with such visit or inquiry,
including but not limited to, any FDA Form 483, Establishment Inspection Reports
or warning letters and (ii) at the same time it provides to any Agency or
regulatory authority, copies of any and all documents, responses or explanations
relating to items set forth above, in each case purged only of trade secrets of
the recipient that are unrelated to the obligations under this Agreement or are
unrelated to Product. In the event such governmental agency or
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authority requests or requires any action to be taken to address any citations,
the recipient agrees, after consultation with the other party, to take such
action as necessary to address such citations, and agrees to cooperate with the
other party with respect to any such citation and/or action taken with respect
thereto.
2.11 INSPECTION BY ESI CIMA shall permit ESI (at its own expense) to
visit, during normal business hours and with reasonable advance notice CIMA's
manufacturing facility(ies) and warehouse, subject to the confidentiality
provisions of this Agreement, for the purposes of (a) observing the manufacture,
packaging, testing and warehousing of Product and to inspect for compliance with
GMP's, applicable regulatory requirements, the requirements of any applicable
Regulatory Approvals, and environmental monitoring, (b) solving technical or
quality problems, (c) examining the premises, equipment, procedures and
personnel used when producing, testing or controlling Product and (d) all books
and records relating to (a), (b) or (c). CIMA representatives shall be entitled
to accompany ESI representatives on any such inspection.
2.12 ENVIRONMENTAL AND OTHER LAWS AND REGULATIONS
(a) In carrying out its obligations under this Agreement, CIMA shall
comply with all applicable environmental, health and safety laws (current or as
amended or added, collectively "Laws"), and shall be solely responsible for
determining how to comply with same. CIMA represents and warrants that it has
the appropriate skills, personnel, equipment, permits or approvals necessary to
perform its services under this Agreement in compliance with all applicable
Laws.
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(b) CIMA shall notify ESI, in writing, no later than one (1) business
day after the event, of any circumstances, including the receipt of any notice,
warning, citation, finding, report or service of process, relating to compliance
with the Laws, or the occurrence of any release, spill, upset or discharge of
"Hazardous Active Ingredients" as defined by the Comprehensive Environmental
Response, Compensation and Liability Act of 1980, as amended, which relates to
CIMA's ability to manufacture or supply Product. ESI reserves the right to
conduct an environmental inspection of CIMA's facility(ies), during normal
business hours and with reasonable advance notice, for the purpose of
determining compliance with this Section 2.12(b), no more frequently than once
per year during the term hereof and under conditions of confidentiality as
provided under Article VIII. Upon CIMA's request, ESI shall share the results of
any environmental inspection with CIMA. Such inspection, if it occurs, does not
relieve CIMA of its sole obligation to comply with the Laws and does not
constitute a waiver of any right otherwise available to ESI.
2.13 SPECIFICATIONS AMENDMENTS The Specifications shall be amended or
supplemented to comply with GMPs and to comply with any applicable Agency
directive and may also be amended or supplemented (including, without
limitation, for the purpose of incorporating improvements) from time to time. In
the event CIMA intends to amend the Specifications, ESI shall receive prompt
advance notice of any such amendments. No such amendment shall be filed with any
applicable Agency or otherwise become effective without the prior written mutual
approval of ESI and CIMA. In the event that after the parties have initially
agreed upon the Specifications, ESI
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requests that the Specifications be amended, CIMA shall receive prompt advance
notice of any such amendment for the purpose of determining what, if any, impact
the proposed amendment would have on the manufacture of Product for ESI
hereunder and ESI shall reimburse CIMA for the actual costs incurred by CIMA
(provided that such costs are approved in writing by ESI prior to being incurred
by CIMA) because such amendment requires changes to be made in the processes,
equipment, testing procedures, or components used to manufacture Product for ESI
hereunder. Such costs may include, without limitation, validation of new
processes, equipment and facilities, development of testing methods and start-up
costs. Any costs incurred by CIMA in implementing an amendment of the
Specifications under this Section shall not be included in CIMA's Direct
Manufacturing Cost.
2.14 APPROVAL FOR MANUFACTURING CHANGES; THIRD PARTY MANUFACTURING CIMA
agrees that no changes will be made to any materials, equipment or methods of
production or testing which are specified in the Specifications or any
Regulatory Approval by any Agency for Product without ESI's prior written
approval, which approval shall not be unreasonably withheld. Under no
circumstances will CIMA contract out all or any part of the manufacturing of
Product to a Third Party without prior written approval from ESI.
2.15 PERMITTED SUBCONTRACTORS CIMA shall ensure that the permitted
contract manufacturers for the manufacture of Product have sufficient knowledge
and expertise to carry out the manufacture of Product and other subcontracted
responsibilities. In addition CIMA shall ensure that (i) each such contract
manufacturer shall be in
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compliance with GMPs and shall be under the inspection of all relevant Agencies
and audited to be in compliance therewith, and (ii) ESI will have the right to
inspect and audit each such subcontractor's facilities and records as provided
in Section 2.11 hereof.
ARTICLE III
ACTIVE INGREDIENT
3.1 SUPPLY OF ACTIVE INGREDIENT
(a) ESI agrees to supply CIMA, at no charge, all Active Ingredient
CIMA requires for the manufacture of Product under this
Agreement and CIMA agrees to use all and only, Active
Ingredient supplied by ESI exclusively in the manufacture of
Product.
(b) As of the time of delivery to CIMA, all Active Ingredient will
conform to the Specifications.
(c) CIMA shall procure all ingredients other than the Active
Ingredient used in the manufacture of Product, including
excipients, inactive ingredients, imprinting materials,
packaging and labeling materials unless otherwise mutually
agreed to by the parties.
(d) CIMA agrees to notify ESI in writing of its requirements for
Active Ingredient in a timely manner so as to assure the timely
filling of ESI's purchase orders for Product. In the event that
ESI fails to have supplied CIMA with sufficient quantities of
conforming Active Ingredient at least sixty days prior to the
due date for delivery of a
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Product order, CIMA will be relieved of its obligation to
timely fill ESI's purchase orders for such Product to the
extent prevented by ESI's failure to have Active Ingredient
timely delivered.
(e) Upon receipt of Active Ingredient, CIMA shall promptly, and in
no event later than thirty (30) business days following
receipt, sample and analyze the same to assure that it complies
with the applicable Specifications. CIMA agrees to provide ESI
with the results of such analysis as soon as reasonably
possible, but in no event later than CIMA's manufacture of
Product containing such Active Ingredient, and to keep, true,
accurate and complete records of all such sampling and
analyses, which records shall at all reasonable times be
available for examination, audit and copying by ESI and its
representatives.
(f) In the event that any Active Ingredient is determined by CIMA
not to be in compliance with applicable Specifications, CIMA
shall immediately notify ESI and shall follow all instructions
of ESI regarding, and be responsible for, re-analysis,
sampling, processing, return, disposal or destruction,
including certification of destruction, of such non-conforming
Active Ingredient.
(g) If CIMA and ESI disagree as to whether any Active Ingredient
meets the applicable Specifications, the matter will be
submitted to an independent testing laboratory, acceptable to
both parties, for
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analysis, which analysis shall be performed in compliance
with applicable regulatory requirements. If the Active
Ingredient is determined to be non-conforming, ESI will
reimburse CIMA for CIMA's out-of-pocket expenses relating
to re-analysis, sampling, processing, returns, disposal
and/or destruction thereof.
3.2 USE OF ACTIVE INGREDIENT
(a) Title to all Active ingredient supplied to CIMA by ESI
shall at all times remain in ESI. CIMA shall clearly mark
such Active Ingredient as the property of ESI and keep such
Active Ingredient separate and apart from other raw
materials.
(b) CIMA shall not at any time sell or offer for sale, assign,
mortgage, pledge, or allow any lien to be created upon the
Active Ingredient provided by ESI or any portion thereof.
(c) At the termination of this Agreement, CIMA shall surrender
to ESI all Active Ingredient in CIMA's possession.
(d) CIMA shall be responsible for all loss or damage, howsoever
occasioned, in Active Ingredient at all times it is in the
possession of CIMA excepting only reasonable loss
necessarily inherent in the manufacturing process. The
parties agree that the amount of Active Ingredient loss
reasonable to the Product's manufacturing process shall in
no event be more than six percent (6%) per batch or more
than four percent (4%) per any twelve month production
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period. CIMA shall permit ESI, during normal business hours
and upon reasonable advance written notice, access to all
records necessary to determine and verify Active Ingredient
loss or damages. CIMA shall reimburse ESI for all costs and
expenses (including shipping costs incurred by ESI in
replacing Active Ingredient lost or damaged but not Active
Ingredient which is determined by on analysis pursuant to
Paragraph 5.1(g) not to be in compliance with the
Specifications.
(e) ESI shall not be liable for any damage, loss or injury
directly or indirectly resulting from the storage or
handling by CIMA of any Active Ingredient.
ARTICLE IV
REGULATORY COMPLIANCE
4.1 ADVERSE DRUG EXPERIENCES In order for the parties to comply with
their respective responsibilities under this Article IV and otherwise relating
to the reporting of Adverse Drug Experiences, to the extent either party
receives any information regarding Adverse Drug Experiences related to use of
Product, such party shall promptly provide the other party with such information
in accordance with the Adverse Event Reporting Procedures set forth in Exhibit B
hereto (as may be amended from time to time upon written agreement of the
parties).
4.2 PRODUCT COMPLAINTS ESI shall be solely responsible for interacting
with the public with respect to customer complaints regarding Product quantity.
With respect
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to any such complaints, each party shall have the responsibility for promptly
conducting an investigation of any activities conducted by it under this
Agreement which may be relevant to the complaint. Each party shall inform the
other party of the nature, scope and details of any such complaint which
requires an investigation by the other party, and each party shall promptly
report the results of such investigation to the other party. Either party shall
cooperate in any investigation by the other party of each such complaint which
involves the parties' duties under this Agreement.
4.3 COMPLIANCE ISSUES The parties acknowledge that the export of
technical data, materials or products is subject to the exporting party
receiving the necessary export licenses and that the parties cannot be
responsible for any delays attributable to export controls which are beyond the
reasonable control of either party. The parties agree that regardless of any
disclosure made by the party receiving an export of any ultimate destination of
any technical data, materials or products, the receiving party will not
re-export either directly or indirectly, any technical data, material or
products without first obtaining the applicable validated or general license
form the United States Department of Commerce.
ARTICLE V
PAYMENT PROVISIONS
5.1 INSPECTION OF RECORDS The parties shall maintain at their offices,
accurate and complete books and records consistent with sound business and
accounting practices and in such form and in such detail as to enable the amount
of payments payable under this Agreement by the respective party to be
determined. ESI and
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CIMA shall permit an independent certified accountant (subject to obligations of
confidentiality) appointed by the other party and reasonably acceptable to ESI
or CIMA(as applicable), at the other party's expense, to examine such books and
records at all reasonable times for the sole purpose of (i) verifying ESI's or
CIMA's (as applicable) reports and accounting submitted to the other party
hereunder and (ii) determining the correctness of payments. In the event of any
underpayment of any payment by at least five percent (5%), the costs of such
inspection shall be borne by the party who made such underpayment and such
underpayment shall be forthwith paid by such party to the other party with
interest at the rate specified in Section 5.3.
5.2 PAYMENTS Each party shall make all payments due to the other party
hereunder by wire transfer in immediately available funds to an account
designated by the payee party.
5.3 INTEREST The parties shall pay interest on any amounts overdue
under this Agreement at a rate equal to the U.S. dollar prime or equivalent rate
quoted by Citibank N.A. or another mutually acceptable bank, as in effect during
the period from the date due until payment.
ARTICLE VI
REPRESENTATIONS AND WARRANTIES
6. REPRESENTATION AND WARRANTIES OF EACH PARTY Each of CIMA and ESI
hereby represents, warrants and covenants to the other party hereto as follows:
(a) it is a corporation or entity duly organized and validly existing
under the laws of the state or other jurisdiction of incorporation or formation;
24
(b) the execution, delivery and performance of this Agreement by such
party has been duly authorized by all requisite corporate action and does not
require any shareholder action or approval;
(c) it has the power and authority to execute and deliver this
Agreement and to perform its obligations hereunder; and
(d) the execution, delivery and performance by such party of this
Agreement and its compliance with the terms and provisions hereof does not and
will not conflict with or result in a breach of any of the terms and provisions
of or constitute a default under (ii)a loan agreement, guaranty, financing
agreement, agreement affecting a product or other agreement or instrument
binding or affecting it or its property (ii) the provisions of its charter or
operative documents or bylaws; or (iii) any order, writ, injunction or decree of
any court or governmental authority entered against it or by which any of its
property is bound.
6.2 REPRESENTATIONS AND WARRANTIES OF CIMA In addition to the
representations and warranties made by CIMA under Section 6.1 above, CIMA hereby
further represents and warrants to ESI that:
(a) At the time of delivery of Product to the specified point of
delivery, Product shall (i) have been manufactured, stored and shipped in
accordance with GMPs, as applicable, and all other applicable laws, rules,
regulations or requirements in effect at the time of manufacture in the country
of manufacture (for example, in accordance with the procedures described in the
applicable Regulatory Approval); (ii) conform to the Specifications; (iii)) meet
the provisions of the Specifications; (iv) shall not be
25
adulterated or misbranded as provided for under any applicable law, order or
regulation in effect in the country of manufacture and the country in which
Product is being sold; (v) shall have been manufactured and have shelf-life in
accordance with [to be discussed]; and (vi) have been shipped in accordance with
approved procedures agreed between ESI and CIMA.
(b) It shall have good and marketable title to all Product delivered to
ESI.
6.3 NO INCONSISTENT AGREEMENTS Neither party has in effect and after
the Effective Date neither party shall enter into any oral or written agreement
or arrangement that would be inconsistent with its obligations under this
Agreement.
6.4 REPRESENTATION BY LEGAL COUNSEL Each party hereto represents that
it has been represented by legal counsel in connection with this Agreement and
acknowledges that it has participated in the drafting hereof. In interpreting
and applying the terms and provisions of this Agreement, the parties agree that
no presumption shall exist or be implied against the party which drafted such
terms and provisions.
ARTICLE VII
INDEMNIFICATION
7.1 INDEMNIFICATION BY ESI ESI shall indemnify, defend and hold
harmless CIMA and its Affiliates, and each of its and their respective
employees, officers, directors and agents (each a "CIMA Indemnified Party") from
and against any all liability, loss, damage, cost and expense (including
reasonable attorney's fees) (collectively, a "Liability") which the CIMA
Indemnified Party may incur, suffer or be required to pay resulting form or
arising in connection with (i) the breach by ESI of any
26
representation or warranty contained in this Agreement, or (ii) the manufacture,
promotion, distribution, use, testing, marketing, sale or other disposition of
Product by ESI, its Affiliates or sublicenses. Notwithstanding the foregoing,
ESI shall have no obligation under this Agreement to indemnify, defend or hold
harmless any CIMA Indemnified Party with respect to claims, demands, costs or
judgments which result from either (x) the failure of Product supplied by CIMA
or its Affiliates to comply with the Specifications or the applicable Regulatory
Approvals or (y) the willful misconduct or negligent acts or omissions of CIMA,
its Affiliates, or any of their respective employees, officers, directors or
agents.
7.2 INDEMNIFICATION BY CIMA CIMA shall indemnify, defend and hold
harmless ESI and its Affiliates, and each of its and their respective employees,
officers, directors and agents (each, an "ESI Indemnified Party") form and
against any Liability which the ESI Indemnified Party may incur, suffer or be
required to pay resulting from or arising in connection with the breach by CIMA
of any representation or warranty contained in this Agreement. Notwithstanding
the foregoing, CIMA shall have no obligation under this Agreement to indemnify,
defend, or hold harmless any ESI Indemnified Party with respect to claims,
demands, costs of judgments which result from the willful misconduct or
negligent acts or omissions of ESI, its Affiliates, or sublicensees or any of
their respective employees, officers, directors or agents.
7.3 CONDITIONS TO INDEMNIFICATION The obligations of the indemnifying
party under Sections 7.1 and 7.2 are conditioned upon delivery of written notice
to the indemnifying party of any potential Liability promptly after the
indemnified party
27
becomes aware of such potential Liability, provided, however, that the failure
to give such notice promptly shall not impair a party's rights to
indemnification under this Article VII unless the delay in providing such notice
has a material adverse effect on the ability of the indemnifying party to defend
against such Liability. The indemnifying party shall have the right to assume
the defense of any suit or claim related to the Liability if it has assumed
responsibility for the suit or claim in writing; however, if in the reasonable
judgment of the indemnified party, such suit or claim involves an issue or
matter which could have a materially adverse effect on the business operations
or assets of the indemnified party, the indemnified party may waive its rights
to indemnity under this Agreement and control the defense or settlement thereof,
but in no event shall any such waiver be construed as a waiver of any
indemnification rights such party may have at law or in equity. If the
indemnifying party defends the suit or claim, the indemnified party may
participate in (but not control) the defense thereof at its sole cost and
expense.
7.4 SETTLEMENTS Neither party may settle a claim of action related to a
Liability without the consent of the other party, if such settlement would
impose any monetary obligation on the other party or require the other party to
submit to an injunction or otherwise limit the other party's rights under this
Agreement. Any payment made by a party to settle any such claim or action shall
be at its own cost and expense except in the event that such payment was made
with the prior written consent of the indemnifying party, in which case such
payment will be subject to the indemnification obligations of the parties as set
forth in this Article VII.
28
7.5 INSURANCE Each party further agrees to obtain and maintain, during
the term of this Agreement, Comprehensive General Liability Insurance, including
Products Liability Insurance, with reputable and financially secure insurance
carriers to cover its indemnification obligations under Section 7.1 or 7.2, as
applicable, or, in the case of ESI, self-insurance, in each case with limits of
not less than five million dollars ($5,000,000.00) per occurrence and ten
million dollars ($10,000,000.00) in the aggregate.
ARTICLE VIII
CONFIDENTIALITY
8.1 NONDISCLOSURE During the Term of this Agreement and for a period of
five (5) years thereafter, all proprietary and confidential business, technical,
scientific and/or regulatory information, including Technical Information,
disclosed to the receiving party or its Affiliates (herein collectively, the
(Receiving Party) by the other party or its Affiliates (herein collectively, the
(Disclosing Party) hereunder or under the existing Confidentiality Agreement
between the parties, which is marked as confidential at the time of disclosure,
or if disclosed or obtained orally or visually (or otherwise in a non-written
form), was described or summarized in a writing or other tangible form and
identified as confidential and forwarded to the Receiving Party within thirty
(30) days of such disclosure (collectively, Confidential Information), shall be
deemed to be confidential and shall be treated as such by the Receiving Party
and shall not be disclosed, in whole or in part, by the Receiving Party to any
other Person except as expressly set forth herein, and shall be used only for
the purposes of this Agreement.
29
Notwithstanding the foregoing these mutual obligations of confidentiality shall
not apply to any information to the extent that such information is:
(i) independently developed by such party as documented by prior
written records outside the scope and not in violation of this Agreement;
(ii) legally in the public domain at the time of its receipt or
thereafter legally becomes part of the public domain through no fault of the
recipient;
(iii) received without an obligation of confidentiality from a Third
Party having the right to disclose such information;
(iv) released from the restrictions of this Article VIII by the express
written consent of the Disclosing Party;
(v) as may be required for securing Regulatory Approval, or as may be
required to be disclosed to an Agency or as otherwise required by a court order
or any law or regulation (including, as may be required in connection with any
filings made with the Securities and Exchange Commission or by the disclosure
policies of a major stock exchange in the Territory); provided, however, that at
the other party's request, the disclosing party shall request that the relevant
legal or regulatory authority, or major stock exchange, treat as confidential
any Confidential Information of either party included in any such disclosure and
generally use diligent efforts to seek confidential treatment where available.
8.2 SCOPE OF CONFIDENTIALITY
CIMA and ESI agree to limit the disclosure of any Technical Information
and other Confidential Information received hereunder to such Affiliates,
employees,
30
consultants and distributors as are necessary to carry out the provisions of
this Agreement and who are likewise bound by provisions equivalent to this
Article VIII, except that, ESI may disclose Confidential Information to actual
or potential sublicenses and subdistributors, provided that they are likewise
bound by confidentiality provisions similar to, or more stringent than, those
set forth in this Article VIII. The parties shall take reasonable measures to
assure that no unauthorized use or disclosure is made by Persons to whom access
to such Confidential Information is granted.
ARTICLE IX
TERM AND TERMINATION
9.1 TERM This Agreement shall be effective as of the Effective Date,
and, unless sooner terminated by mutual agreement or pursuant to any other
provision of this Agreement, shall continue in full force and effect in each
country of the Territory for a period of ten (10) years after the Launch Date of
Product in the first Major Country of the Territory which shall be deemed to
occur no later than six (6) months after obtaining Regulatory Approval or where
applicable, Pricing Approval, in the first Major Country of the Territory (the
Initial Term). After the Initial Term, this Agreement shall be automatically
renewed for successive two (2) year periods (each, an Extended Term), unless ESI
notifies CIMA of ESI's intent not to renew this Agreement at least nine (9)
months prior to the expiration of the Initial Term or the then current Extended
Term. The Term shall include the Initial Term and any Extended Term. If the
Development and
31
License Agreement is terminated for any reason other than expiration, then this
Agreement shall automatically terminate.
9.2 TERMINATION FOR DEFAULT Each party may terminate this Agreement as
a whole if the other party commits a material breach of any material obligation
under this Agreement and fails to remedy such breach within sixty (60) days (or,
in the case of a late payment, ten (10) business days of notice of such breach,
or other longer period of time if mutually agreed.
9.3 TERMINATION BY ESI ESI shall have the right, in its sole
discretion, to terminate this Agreement at any time during the Term of this
Agreement upon six (6) months' prior written notice to CIMA.
9.4 NO DAMAGES UPON EXPIRATION OR TERMINATION Except as otherwise set
forth in this Agreement, neither party shall be entitled to any compensation
whatsoever as a result of expiration or termination of this Agreement, but
without limiting either party's damages for any breach of this Agreement.
9.5 CONTINUING OBLIGATIONS Termination or expiration of this Agreement
for any reason shall be without prejudice to any obligations which shall have
accrued to the benefit of either party prior to such termination or expiration.
Upon termination or expiration of this Agreement, any payments owed to the other
party on or before the effective date of termination would be due within thirty
(30) days of the effective date of such termination or expiration. The following
provisions of this Agreement shall survive expiration or termination hereof:
Articles VIII, IX, and XI.
32
ARTICLE X
PUBLICATIONS
10.1 PUBLICATIONS The parties shall mutually agree upon publications
and the publication strategy with respect to work undertaken by the parties
relating to Product, and neither party shall publish any result or study
generated or developed under this Agreement except upon review by the other
party at least sixty (60) days prior to submission of an abstract or manuscript
for publication.
ARTICLE XI
MISCELLANEOUS
11.1 FORCE MAJEURE Neither party shall be liable for delay or failure
to perform its obligations hereunder for so long as that failure or delay is the
result of an event beyond its control which it could not have avoided by the
exercise of reasonable diligence, (a force majeure event), provided that such
party uses Commercially Reasonable Efforts to comply with the terms of this
Agreement as soon as practicable. A party asserting a force majeure event shall
notify the other party promptly, giving an indication of the likely extent and
duration thereof.
11.2 ASSIGNMENT; SUCCESSORS AND ASSIGNS Neither party shall at any
time, without obtaining the prior written consent of the other party, assign or
transfer this Agreement to any Person. Notwithstanding the foregoing, each party
shall be permitted to assign this Agreement to its Affiliates or to perform this
Agreement, in whole or in part, through its Affiliates, provided that such party
shall be primarily liable and
33
responsible for performance by such Affiliate hereunder; and each party may also
assign this Agreement to any successor by merger or upon a sale of all or
substantially all of its assets. This Agreement shall be binding upon and shall
inure to the benefit of the parties and their successors and permitted assigns.
11.3 NOTICES Any notices required or permitted to be given hereunder
shall be in writing in the English language and shall be delivered by
international courier service (requiring signature upon receipt) or sent by
first class air mail, postage prepaid, or telefax (confirmed by phone
conversation with the recipient) to the addresses set forth below. The parties
may change the address at which notice is to be given by giving notice to the
other party as herein provided. All notices shall be deemed effective upon
receipt by the party to whom it is addressed.
If to CIMA: CIMA, Labs. Inc.
10000 Valley View Road
Eden Prairie, MN 55344
Attention: Dr. John Siebert
President and CEO
Telephone: (612) 947-8762
Telefax: (612) 947-8770
34
If to ESI: With a copy to:
ESI Lederle American Home Products Corporation
130 North Radnor-Chester Road 5 Giralda Farms
St. Davids, Pennsylvania 19087 Madison, New Jersey 07940
Attention: President Attention:
Telephone: (610) 971-4550 Senior Vice President & General Counsel
Telefax: (610) 995-3394 Telephone: (973) 660-6040
Telefax: (973) 660-7050
11.4 GOVERNING LAW AND JURISDICTION This Agreement and its execution,
validity and interpretation shall be governed in all respects in accordance with
the laws of the State of New York, excluding conflicts of law rules.
11.5 SEVERABILITY In the event that any provision of this Agreement
shall be held to be unenforceable, invalid or in contravention of applicable
law, such provision shall be of no effect, and the parties shall negotiate in
good faith to replace such provision with a provision which effects to the
extent possible the original intent of such provision.
11.6 COMPLETE AGREEMENT; MODIFICATIONS This Agreement, together with
the Development and License Agreement and all Exhibits attached to each,
constitutes the entire Agreement between the parties with respect to the present
subject matter, all prior negotiations, agreements and understandings being
expressly canceled hereby. This Agreement may be amended only by a written
agreement embodying the full terms of the amendment signed by authorized
representatives of both parties.
11.7 NO AGENCY Neither party shall by virtue of this Agreement have any
power to bind the other to any obligation nor shall this Agreement create any
relationship of agency, partnership or joint venture.
35
11.8 NO WAIVER No term or condition of this Agreement shall be
considered waived unless reduced to writing and duly executed by an officer of
the waiving party. Any waiver by any party of a breach of any term or condition
of this Agreement will not be considered as a waiver of any subsequent breach of
this Agreement, of that term or condition or any other term or condition hereof.
11.9 COUNTERPARTS This Agreement may be executed in counterparts, each
of which together shall constitute one and the same Agreement.
IN WITNESS WHEREOF, the parties have executed this Agreement as of the
date first above written.
CIMA LABS INC. ESI LEDERLE
By: /s/ John M. Siebert By: /s/ Mike Dey
Name: John M Siebert Name: Mike Dey
Title: President and CEO Title: President
36
EXHIBIT A
SPECIFICATIONS
The Specifications are set forth in the following four pages.
37
CIMA LABS, INC. (R)
Raw Materials Specifications
Loratadine, Micronized
COMPONENT #: 20-46837-900 APPROVED: (Quality Control)
-----------
EFFECTIVE DATE: 11-26-99 APPROVED: (Materials)
------------------
SUPERSEDES: 11-2-99 APPROVED: (Product Compliance)
---------
PURCHASING SPECIFICATIONS All materials must meet CIMA specifications.
SUPPLIER/MANUFACTURER Quimical Sintetica, S.A.
SHIPPING SPECIFICATIONS 50-kg Double poly-lined, fiber drums
MATERIAL IDENTIFICATION Marking must show product name, manufacturer's name,
manufacturer's lot number, CIMA purchase order number,
CIMA component number, and quantity per container.
SAFETY PRECAUTIONS Refer to Material Safety Data Sheets
SAMPLING In accordance with SOP 360070
SAMPLE SIZE 300 g SOP 360006
RETEST DATE Annually from date of receipt SOP 360015
RETEST SAMPLE SIZE 75 g SOP 360006
EXPIRATION DATE Five years from the date of manufacture SOP 360015
SAMPLE RETENTION 225 g SOP 360016
STORAGE CONDITIONS Store in sealed containers at ambient
warehouse conditions.
REFERENCE Manufacturer's COA
ATTACHMENTS A. Raw Material Worksheet
These specifications are agreeable to the supplier/manufacturer unless exception
is made in writing. These are the governing factors pertaining to the quality
of material shipped against all orders placed on or after the date of these
specifications.
Specifications
Loratadine 10 MG Orally disintegrating Tablets
Formulation No. CL-099-02 Specification No. R-0105-00
SPECIFICATION (THROUGH SHELF LIFE)
TEST SPECIFICATION TEST METHOD
- --------------------------------------------------------------------------------------------------
Physical Appearance White to off-white, flat-faced, 3/8", round,
beveled tablet ATM-123
Identity* Positive for Loratadine
1) HPLC ATM-276
2) IR ATM-281
Assay (90.0 - 110.0%) 9.00 - 11.00 mg/tablet ATM-276
1) NMT 0 Tabs +- 15% label claim (8.50-11.50
mg/tab) and % RSD < 6.0%; (n =10) ATM-275
-
2) NMT 0 Tabs +- 25% label claim (7.50-12.50
mg/tab) and NMT 1 Tabs +- 15% label claim
(8.50-11.50 mg/tab) and % RSD < 7.8%; (n =30)
-
Water content by KF Record ATM-279
Dissolution NLT 80% (Q) at 15 minutes ATM-272
1) S1 (n=6) Each individual tablet NLT 85% at
15 minutes.
2) S2 (n=12) Average of 12 tablets (S1+S2) NLT
80% at 15 minutes. Each individual tablet
NLT 65% at 15 minutes.
3) S3 (n=24) Average of 24 tablets (S1+S2+S3) NLT
80% at 15 minutes. NMT 2 tablets less than
65% and no tablets less than 55% at 15 minutes.
Related substances:
Impurity I Record ATM-280
Impurity II Record
Impurity III Record
Impurity IV Record
Impurity V Record
Individual Other Record
Total Record
* Test performed at initial release only; product maintains specification
throughout shelf life.
Specifications
Loratadine 10 MG Orally disintegrating Tablets
Formulation No. CL-099-02 Specification No. R-0105-00
History
REVISION NO. CHANGES ORIGINATOR
- ---------------------------------------------------------------------------
00 Original Walid Habib/
Jim Klancke
Loratadine Packaging Specifications
Subject to modifications as determined by Wyeth-Ayerst and CIMA Packaging and
Regulatory Affairs staff.
- - Each blister card will contain 6 blisters.
- - Each carton will contain 5 blister cards.
- - Each case will contain 24 to 48 cartons.
- - The label for carton will come from ESI Lederle, and will have a barcode for
that NDC as well as additional information.
- - Each blister card will have the following printed on it:
1. Name of product
2. Name of active
3. Name of manufacturer
4. Lot number
5. Expiration date
6. NDC
7. Directions of opening
38
EXHIBIT B
ADVERSE EVENTS
ADVERSE EXPERIENCE REPORTING PROCEDURES
The parties hereby agree that the following terms will govern
disclosures of each party to the other with respect to adverse event reporting
relating to Product as clinically tested or marketed by or on behalf of either
party.
1. DEFINITIONS.
1.1 ADVERSE EXPERIENCE OR EVENT (AE): An AE is defined by ESI as any
untoward, undesired, or unplanned event in the form of signs,
symptoms, disease, or laboratory or physiological observations
occurring in a human being in a temporal relationship to use of a
ESI product regardless of causal relationship. This includes:
- any clinically significant worsening of a pre-existing
condition;
- an AE occurring from overdose (i.e., a dose higher than that
prescribed by a health care professional for clinical reasons)
of a ESI product, whether accidental or intentional;
- an AE occurring from abuse (i.e., use for non-clinical reasons)
of a ESI product;
- an AE that has been associated with the discontinuation of the
use of a ESI product;
- any failure of expected pharmacological action (for spontaneous
reports).
If there is any doubt whether the information constitutes an AE,
the information will be treated as an AE.
1.2 SERIOUS AE: A serious AE is defined by ESI as an AE occurring at
any dose that: results in death; is life-threatening (see below);
requires inpatient hospitalization or prolongation of an existing
hospitalization; results in a persistent or significant disability
or incapacity (see below); results in cancer; results in a
congenital anomaly or birth defect. Additionally, IMPORTANT MEDICAL
EVENTS that may not result in death, be life-threatening, or
require hospitalization may be considered a serious AE when, based
upon appropriate medical judgment, they may jeopardize the patient
or subject and may require medical or surgical intervention to
prevent one of the outcomes listed in this definition. Examples of
such medical events
39
include allergic bronchospasm requiring intensive treatment in an
emergency room or at home; blood dyscrasias or convulsions that do
not result in hospitalization; or the development of drug
dependency or abuse.
1.2.1 Life-threatening refers to immediate risk of death as the
event occurred. A life-threatening experience does not
include an experience that, had it occurred in a more severe
form, might have caused death but as it actually occurred did
not create an immediate risk of death. For example, hepatitis
that resolved without evidence of hepatic failure would not
be considered life-threatening even though hepatitis of a
more severe nature can be fatal. Similarly, an allergic
reaction resulting in angioedema of the face would not be
life-threatening, even though angioedema of the larynx,
allergic bronchospasm, or anaphylaxis can be fatal.
1.2.2 Disability is defined as a substantial disruption in a
person's ability to conduct normal life functions.
1.2.3 For studies, all pregnancies and all overdoses will be
reported to GSSE in the same time frame as serious AEs.
1.2.4 A serious AE obtained from tests in laboratory animals
includes any experience suggesting a significant risk for
human subjects, including any findings of mutagenicity,
teratogenicity, or carcinogenicity.
1.2.5 If there is any doubt whether the information constitutes a
serious AE, the information will be treated as a serious AE.
1.3 NON-SERIOUS AE: is any AE which does not meet the criteria for a
serious AE.
1.4 UNEXPECTED AE: An unexpected AE is one that is not listed in the
current product labeling. The current product labeling is either
the package insert (for marketed ESI products) or the current
investigator's brochure (for investigational ESI products). An
unexpected AE includes any event that may be symptomatically and
pathophysiologically related to an event listed in the labeling,
but differs from the labeled event because of greater severity or
specificity. For example, hepatic necrosis would be unexpected (by
virtue of greater severity) if the product labeling referred only
to elevated hepatic enzymes or hepatitis. Similarly, cerebral
thromboembolism and cerebral vasculitis would be unexpected (by
virtue of greater specificity) if the labeling only listed cerebral
vascular accidents.
1.5 PRODUCT (DRUG, VACCINE, BIOLOGICAL, DEVICE)-RELATED: For the
purposes of regulatory reporting for investigational products, an
AE will be considered "product-related" (i.e., drug-related,
vaccine-related, etc.) for studies if either the investigator, the
Medical Monitor, the CR&D Clinical Project Team Medical
40
Monitor (or designee), OR the Local Monitor (if applicable)
assesses the AE(s) as possibly, probably, or definitely related.
1. An AE will be considered "not product-related" for studies if
the investigator AND the medical monitor(s) AND the local
monitor (if applicable) assess the AE(s) as probably not related
or definitely not related, or "relationship remote."
2. Whenever the investigator's or monitor's assessment is unknown
or unclear, the AE(s) will be treated as product-related for the
purposes of reporting to regulatory authorities.
1.6 PROTOCOL-RELATED: AEs from studies that are not product-related may
nevertheless be considered by the investigator OR the medical
monitor(s) OR the local monitor (if applicable) to be
protocol-related. For purposes of reporting to GSSE and regulatory
authorities, these will be reported in the same manner as
product-related events.
1.7 NDA HOLDER is defined as: An "Applicant" as defined in 21 CFR Part
314.3(b), for regulatory approval of a Product in any regulatory
jurisdiction, including a holder of a foreign equivalent thereto.
1.8 IND HOLDER is defined as: A "Sponsor" as defined in 21 CFR Part
313.1(b) of an investigational new drug in any regulatory
jurisdiction, including a holder of a foreign equivalent thereto.
1.9 Capitalized terms not defined in this Exhibit shall have the
meaning assigned thereto in the Agreement.
2. With respect to the Product or Active Ingredient, the Parties agree as
follows:
a. All initial reports and any follow-up information (oral or written)
for any and all Serious AEs as defined above, (other than with
respect to animal studies) which become known to either Party
(other than from disclosure by or on behalf of the other Party)
must be communicated by telephone, telefax or electronically
directly to the other Party and/or the NDA Holder, IND Holder
(individually and collectively referred to as "Holders") within
forty-eight (48) hours of receipt of the information. Written
confirmation of the Serious AE received by such Party should be
sent to the other Party and/or the Holders as soon as it becomes
available, but in any event within forty-eight (48) hours of
initial report of the Serious AE by such Party.
b. Both Parties shall exchange Medwatch and/or CIOMs forms and other
health
41
authority reports within forty-eight (48) hours of submission to
any Regulatory Authority.
c. All initial reports and follow-up information received for all
Non-Serious AEs for marketed Product which become known to a Party
(other than from disclosure by or on behalf of the other Party)
must be communicated in writing, by telefax or electronically to
the other Party within ten (10) days, on Medwatch or CIOMs forms
(where possible).
d. Each Party shall coordinate and cooperate with the other whenever
practicable to prepare a single written report regarding all
Serious and/or Non-Serious AEs, provided, however, that neither
Party shall be obligated to delay reporting of any AE in violation
of applicable law or regulations regarding the reporting of AEs.
3. The Parties further agree that:
a. A written report be forwarded to the other Party within forty-eight
(48) hours of receipt by the Party making the report, for AEs for
animal studies which suggest a potential significant risk for
humans;
b. Each Party will give the other Party a report via a print-out or
computer disk of all AEs reported to it and its Affiliates relating
to the Product or Active Ingredient within the last year, within
thirty (30) days of receipt of a request from the other Party but
not more often than four (4) times a year;
c. If either Party wishes access to AE Reports of the other Party
relating to the Product or Active Ingredient, upon request of that
Party, the other Party shall make available its AE records relating
to the Product or Active Ingredient (including computer disks) for
viewing and copying by the other Party. The Parties may discuss the
transfer of AE Reports by computer disk.
d. Disclosure of information hereunder by a Party to the other Party
shall continue as long as either Party and/or its Affiliates or
designees continue to clinically test or market Product or Active
Ingredient.
4. Each Party shall diligently undertake the following further obligations
where both Parties are or will be commercializing the Product or Active
Ingredient pursuant to the Agreement and/or performing clinical trials
with respect to the Product or Active Ingredient:
a. Upon the Effective Date, each Party shall identify individuals who
shall be responsible for identifying all AE reporting requirements
in all countries of the Territory as set forth in the Agreement,
and any amendments thereto;
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b. To immediately consult with the other Party, with respect to the
investigation and handling of any Serious AE disclosed to it by the
other Party or by a third Party and to allow the other Party to
review the Serious AE and to participate in the follow-up
investigation;
c. To immediately advise the other Party of any Product and/or Active
Ingredient safety communication received from a health authority
and consult with the other Party with respect to any Product and/or
Active Ingredient warning, labeling change or change to an
investigators' brochure involving safety issues proposed by the
other Party, including, but not limited to the safety issues agreed
to by the Parties;
d. To diligently handle in a timely manner the follow-up investigation
and resolution of each AE reported to it;
e. To provide the other Party mutually agreed upon audit rights of its
AE reporting system and documentation, upon prior notice, during
normal business hours, at the expense of the auditing Party and
under the confidentiality obligations set forth in the Agreement;
f. To meet in a timely fashion from time to time as may be reasonably
required to implement the adverse event reporting and consultation
procedures described in this Exhibit, including identification of
those individuals in each Party's Drug Safety group who will be
responsible for reporting to and receiving AE information from the
other Party, and the development of a written standard operating
procedure with respect to adverse event reporting responsibilities,
including reporting responsibilities to investigators;
g. Where possible, to transmit all data electronically;
h. to report to each other any addenda, revisions or changes to the
Agreement (e.g., change in territories, local regulations, addition
of new licensors/licensees to the Agreement, etc.) which might
alter the adverse event reporting responsibilities hereunder;
i. to utilize English as the language of communication and data
exchange between the Parties;
j. to develop a system of exchange of documents and information in the
event that the Agreement involves more than two Parties;
k. to work together to develop an electronic system to transmit AE
data.
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5. The parties may meet after the Effective Date of the Agreement to
establish a separate agreement for adverse event exchange which will
supersede this Exhibit.