Distribution and Supply Agreement - Smithkline Beecham Corp. d/b/a GlaxoSmithKline and Celgene Corp
CONFIDENTIAL
DISTRIBUTION AND SUPPLY AGREEMENT
BY AND BETWEEN
SMITHKLINE BEECHAM CORPORATION, D/B/A/GLAXOSMITHKLINE
AND
CELGENE CORPORATION
MARCH 31, 2003
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DISTRIBUTION AND SUPPLY AGREEMENT
This DISTRIBUTION AND SUPPLY AGREEMENT (this "Agreement") is made and
entered into as of March 31, 2003, by and between SmithKline Beecham
Corporation, d/b/a/ GlaxoSmithKline, a corporation duly organized and existing
under the applicable laws of the Commonwealth of the State of Pennsylvania,
having a principal place of business in Philadelphia, Pennsylvania ("GSK"), and
Celgene Corporation, a corporation duly organized and existing under the
applicable laws of the State of New Jersey, and having a principal place of
business in Warren, New Jersey ("Celgene").
RECITALS
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WHEREAS, GSK owns the marketing and distribution rights to the
prescription pharmaceutical products sold under the Alkeran(R) brand in various
formulations, presentations and strengths; and
WHEREAS, Celgene wishes to obtain the exclusive right to distribute,
even as to GSK, market, promote, detail, advertise and sell the Products (as
hereinafter defined) as GSK's exclusive distributor of such Products in the
Territory (as hereinafter defined), and to utilize GSK's Trademarks (as
hereinafter defined) to identify the Products in connection with the
distribution, marketing, promotion, advertisement and sale of the Products in
the Territory as described herein, and GSK wishes to grant such rights to
Celgene on the terms and conditions set forth in this Agreement; and
WHEREAS, Celgene wishes to purchase from GSK, and GSK agrees to supply
to Celgene, Celgene's entire requirements of the Products, for distribution in
the Territory for the Term (as hereinafter defined).
NOW, THEREFORE, in consideration of the mutual covenants and agreements
hereinafter set forth and other good and valuable consideration, the receipt and
legal sufficiency of which are hereby mutually acknowledged, GSK and Celgene
hereby agree as follows:
ARTICLE 1
DEFINED TERMS
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1.01 Defined Terms. The following terms, whether used in the singular
or plural, shall have the meanings assigned to them below for purposes of this
Agreement:
"Actual Quantity" has the meaning set forth in Section
5.03(c).
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"Adverse Event" shall mean any adverse event associated with
the use of the Products in humans, whether or not considered drug-related,
including (i) an adverse event occurring in the course of the use of the
Products in professional practice; (ii) an adverse event occurring from an
overdose, whether accidental or intentional, related to the Products; (iii) an
adverse event occurring from drug abuse related to the Products; (iv) an adverse
event occurring from withdrawal of the Products; and (v) any failure of expected
pharmacological action, or such other definition as may from time to time be set
forth in 21 CFR Part 314.80.
"Affiliate" means, with respect to any person, any other
person, that directly or indirectly controls, is controlled by, or is under
common control with, such person. For such purposes, control, controlled by and
under common control with shall mean the possession of the power to direct or
cause the direction of the management and policies of an entity, whether through
the ownership of voting stock or partnership interest, by contract or otherwise.
In the case of a corporation, the direct or indirect ownership of fifty percent
(50%) or more, or the ownership percentage as required under local jurisdiction,
of its outstanding voting shares or the ability otherwise to elect a majority of
the board of directors or other managing authority of the entity shall in any
event be deemed to confer control, it being understood that the direct or
indirect ownership of a lesser percentage of such shares shall not necessarily
preclude the existence of control.
"Agreement" means this agreement, together with all
appendices, exhibits and schedules hereto, as the same may be amended or
supplemented in accordance with this Agreement.
"Alkeran(R)"means the Products (as defined below).
"Annual Minimum Purchase Requirement" has the meaning set
forth in Section 5.01(b).
"Annual Period" means any of the four periods identified as
such in the table in Section 5.01(b) and, if the Term of this Agreement is
extended pursuant to Section 12.01, each twelve (12) month period ending on the
anniversary of March 31, 2006.
"Applicable Laws" means all laws (including the common law),
ordinances, rules and regulations applicable to this Agreement or the activities
contemplated hereunder, including without limitation the Federal Food, Drug, and
Cosmetic Act and applicable regulations, federal and state anti-kickback laws,
privacy laws, consumer protection statutes, laws relating to sample
accountability and any requirements under any Product Registrations applicable
to the Products in the Territory.
"Applicable Percentage" has the meaning set forth in Section
5.05(a).
"Average Annual Net Sales" has the meaning set forth in
Section 12.07.
"Business Day" means any day that is not a United States
federal holiday.
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"Calendar Quarter" means a period of three (3) consecutive
calendar months commencing each January 1, April 1, July 1, and September 1 and
ending each December 31, March 31, June 30 and September 30, as the case may be.
"Celgene Claim" has the meaning set forth in Section 9.01.
"Celgene Party" has the meaning set forth in Section 9.01.
"Commercially Reasonable Efforts" of a Party means those
efforts consistent with the exercise of its prudent scientific and business
judgment as applied to other commercialization efforts for products of similar
scientific and commercial potential within the relevant product lines of such
Party.
"Confidential Information" has the meaning set forth in
Section 11.01(a).
"Confidentiality Agreement" has the meaning set forth in
Section 11.01(b).
"Cost of Goods" means the price at which Celgene purchases
Products from GSK, as set forth in Section 5.05.
"CSO" means a contract sales organization that is engaged in
the business of promoting prescription drug products.
"DDMAC" means the FDA's Division of Drug Marketing,
Advertising and Communications.
"Delivery Date" has the meaning set forth in Section 5.03(b).
"Effective Date" means the date upon which this Agreement was
first entered into, as set forth above. "Existing Inventory" means GSK's entire
finished goods inventory of Products in the Territory as of the end of the
Transition Period in an amount not to exceed the quantity of the Products
specified in the Purchase Order referred to in Section 5.02(a)(i) less
quantities shipped by GSK during the Transition Period pursuant to Section
3.08(a).
"FDA" means the United States Food and Drug Administration, or
any successor agency of the United States.
"Federal Programs" has the meaning set forth in Section 3.07.
"GLP" has the meaning set forth in Section 8.02(f)(ii).
"Good Manufacturing Practices" means all current good
manufacturing practices as defined under 21 USC ss. 351(a)(2)(B) and the FDA
regulations promulgated thereunder, as in effect from time to time.
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"Governmental Authority" means any Federal, state, local or
foreign governmental authority, agency or other body.
"GSK Claim" has the meaning set forth in Section 9.02.
"GSK Entities" means GSK and those GSK Affiliates that
manufacture, distribute, sell, promote or market the Products in the Territory.
"GSK Party" has the meaning set forth in Section 9.02.
"Intellectual Property" means: (i) all patents and patent
applications in existence as of the Effective Date, as set forth on EXHIBIT
1.01A
"Manufacturing Documentation" means, with respect to any
Product, any and all current validation reports, any current formulation's
manufacturing instructions, and current batch record templates, and which are
specific to or otherwise used in Secondary Manufacture of the finished form of
the Product. For avoidance of doubt, it is understood and agreed that the term
"Manufacturing Documentation" shall only apply to such documents as are used in,
or that relate to, the finished goods manufacturing process, and shall not in
any case apply to the Primary Manufacturing process or to the synthesis of any
of the active drug substance in the Product.
"Material Adverse Effect" has the meaning set forth in Section
8.02(b).
"NDA" means a New Drug Application filed with the FDA for any
product, requesting permission to place a drug on the market in accordance with
21 CFR Part 314, and all amendments or supplements filed pursuant to the
requirements of the FDA, including all documents, data and other information
concerning such product which are necessary for FDA approval to market such
product in the Territory.
"NDC" means National Drug Code.
"Net Sales" means the gross amount invoiced for Products by
Celgene or its Affiliates to Third Parties in the Territory, less:
(i) quantity, trade, and/or cash discounts, allowances,
rebates, chargebacks and price adjustments or reductions allowed or given;
(ii) credits, rebates, chargebacks, or refunds allowed for
rejected, outdated, damaged, or returned Products;
(iii) the Cost of Goods; and
(iv) any other similar and customary deductions as defined and
accepted by U.S. Generally Accepted Accounting Principles.
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Deductions shall be determined in accordance with U.S. Generally Accepted
Accounting Principles, consistently applied. If any of the Products are sold for
compensation other than cash, Net Sales shall be calculated based on the gross
list price of the Products on the date of sale in cash.
"Net Wholesale Price" means the gross list price published by
Celgene, ex-factory, to its wholesale customers for the Products.
"Party" means GSK or Celgene and, when used in the plural,
shall mean GSK and Celgene.
"PDMA" means the Prescription Drug Marketing Act.
"Person" means any natural person, corporation, firm, business
trust, joint venture, association, organization, company, partnership, limited
liability company, or other business entity, or any government or any agency or
political subdivision thereof (including but not limited to FDA).
"Pre-Clearance Period" has the meaning set forth in Section
3.02(b)(ii).
"Pre-Clearance Process" has the meaning set forth in Section
3.02(b)(ii).
"Primary Manufacture" or "Primary Manufacturing" means the
process used in the manufacture of an active drug substance (including, but not
limited to the synthesis thereof), the result of which will be used in Secondary
Manufacturing of a pharmaceutical product.
"Products" means melphalan in all dosage forms, formulations,
line extensions and package configurations comprising melphalan as an active
ingredient marketed by GSK or its Affiliate in the Territory under the tradename
Alkeran(R) and any improvements to such formulations or dosages as may hereafter
be distributed by GSK or its Affiliates in the Territory during the Term for the
treatment of multiple myeloma and non-resectable epithelial carcinoma of the
ovary.
"Product Packaging Materials" means all packaging materials
used in the manufacture of, and shipment of, the Products, as in effect on the
date hereof, including primary and secondary containers, closures, tertiary
packaging materials, labels and leaflets, all as revised from time to time in
accordance with the terms and conditions of this Agreement.
"Product Registration" means the approvals or registrations
for any of the Products which have been received by GSK in the Territory,
including without limitation the Drug Master File (DMF) and NDA for the Product.
"Promotional Review Notice" has the meaning set forth in
Section 3.02(b)(i).
"Purchase Order" has the meaning set forth in Section 5.02(a).
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"Recall" has the meaning set forth in Section 6.07.
"Renewal Date" has the meaning set forth in Section 12.01.
"Secondary Manufacture" or "Secondary Manufacturing" means the
manufacturing and packaging process used in formulating the active drug
substance and all excipients into a final dosage form of a pharmaceutical
product.
"Semi-Annual Supply Schedule" has the meaning set forth in
Section 5.02(c).
"Serious Adverse Event" means an Adverse Event occurring at
any dose that results in any of the following outcomes: death, a
life-threatening Adverse Event, inpatient hospitalization or prolongation of
existing hospitalization, a persistent or significant disability/incapacity, or
a congenital anomaly/birth defect. Important medical events that may not result
in death, be life-threatening, or require hospitalization may be considered a
Serious Adverse Event 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.
"Term" has the meaning set forth in Section 12.01.
"Territory" means the United States of America, excluding its
territories and possessions.
"Third Party" means any Person whom or which is neither a
Party nor an Affiliate of a Party.
"To The Knowledge of" a specified entity or any similar term
means to the actual knowledge of the officers of the specified entity having
operating responsibility for the business of such entity.
"Trademarks" means the trademarks set forth on EXHIBIT 1.01B.
"Transition Period" means the period commencing on the
Effective Date and ending on a date, which shall be designated by Celgene in
writing at least fifteen (15) Business Days prior to such date, that is no later
than nine (9) months after the Effective Date, determined by Celgene, in its
sole discretion to be the date by which Celgene has or shall have sufficient
warehousing capabilities such that the services contemplated by the provisions
of Section 3.08 are no longer necessary. Any extension of the Transition Period
shall be upon mutual agreement, in writing, by the Parties.
1.02 Terms Generally. All references herein to Articles, Sections,
paragraphs, clauses, Exhibits and Schedules shall be deemed references to
Articles, Sections, paragraphs and clauses of this Agreement and Exhibits and
Schedules to this Agreement unless the context shall otherwise require.
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ARTICLE 2
APPOINTMENT OF DISTRIBUTOR; RIGHTS AND LIMITATIONS;
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RIGHTS OF FIRST REFUSAL FOR THE PRODUCTS
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2.01 Appointment of Distribution Rights. (a) Subject to the terms and
conditions of this Agreement, GSK hereby appoints Celgene as GSK's exclusive
distributor (exclusive even as to GSK and its Affiliates) of the Products in the
Territory, and, in connection therewith, grants to Celgene the exclusive right
(exclusive even as to GSK and its Affiliates) to market, promote, advertise,
sell and distribute the Products in the Territory. The appointment made in the
preceding sentence shall commence as of the Effective Date and continue
throughout the Term, and shall not survive past the termination or expiration of
the Term. GSK and its Affiliates shall not engage in any marketing, promotion,
advertisement, sale or distribution (except to the extent provided in Section
2.01(b) below) of the Products within the Territory during the Term of this
Agreement. GSK shall not knowingly sell to any of its Affiliates or any Third
Party outside the Territory Products for resale inside the Territory.
(b) GSK shall retain the right to ship Products through its
distribution channels in the Territory, as long as such shipment is solely in
connection with providing Products to GSK Affiliates for sale outside the
Territory or to Celgene within the Territory.
(c) Celgene and GSK shall cooperate with each other to effect a smooth
transition to Celgene of GSK's customers for the Products in the Territory.
Attached hereto as EXHIBIT 2.01 is a list of GSK's contract holders for the
Products in the Territory.
(d) In order to ensure a smooth transition to Celgene of GSK's
customer's for the Products in the Territory, GSK and Celgene shall send a
letter to all GSK customers within twenty-four hours of the Effective Date
informing such customers that Celgene is the exclusive distributor of the
Products in the Territory from and after the Effective Date. A copy of such
letter is attached hereto as EXHIBIT 2.01(d).
2.02 Territorial Limitation. Celgene agrees that it shall conduct its
marketing, promotion, advertisement, sale and distribution of the Products
solely in the Territory. Celgene shall not sell, market, promote, advertise or
distribute the Products outside the Territory. Celgene shall not knowingly sell
the Products, directly or indirectly, to any Third Party in the Territory for
resale outside the Territory. It is acknowledged by the parties, however, that
certain sales of the Products by Celgene to the United States Government, and
its subdivisions thereof, may result in the Products being shipped to military
bases and other government installations that are outside the scope of the
Territory and such sales shall not constitute a breach of this Agreement. GSK
shall use Commercially Reasonable Efforts to ensure that its Affiliates shall
not sell the Products, directly or indirectly, to Third Parties in the Territory
for commercial sale.
2.03 Restriction on Sub-Distributors. Without the prior written consent
of GSK, Celgene shall not grant to any Third Party any rights to market,
promote, advertise, sell or distribute the Products, and shall not enter into
any agreement or arrangement with respect to co-
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promoting the Products. The foregoing notwithstanding, Celgene may employ the
services of a Third Party in (a) the detailing of the Products to healthcare
professionals in the Territory, so long as any sales representative deployed by
such Third Party for Celgene for such purpose shall at such time not detail
products that are competitive with the Products, (b) the receiving, warehousing
and shipping of the Products for Celgene, or (c) the acceptance of orders,
generation of invoices and collection and management of receivables with respect
to Celgene's sales of the Products.
2.04 Compliance with Product Registration Resale in Same Packaging.
Celgene shall not at any time do, and neither shall Celgene permit its agents or
representatives to do, any act in violation of the Product Registration for any
of the Products in the Territory. In the event that any filings are required to
be made with or approvals required to be obtained from applicable regulatory
authorities in order to sell the Products to Celgene or for Celgene to initiate
distribution, marketing, advertisement, sale or promotion of the Products in the
Territory, the Parties shall cooperate fully to ensure that such filings and
approvals are obtained or made as expeditiously as reasonably practicable.
Celgene shall not alter in any manner any of the Products or its packaging as
sold to it by GSK hereunder and shall resell the Products without alteration in
the form sold to it by GSK.
2.05 No Ownership Rights Conveyed on Effective Date. Except for
Celgene's right to use the Trademarks pursuant to Section 3.03 hereof, no right
or license under any Trademark, or under any patent rights or know-how owned or
controlled by GSK or any of its Affiliates to make or have made the Products is
granted under this Agreement to Celgene. Without limiting the foregoing, the
Parties acknowledge and agree that nothing in this Agreement shall grant to
Celgene any right or interest in any new Products, dosage forms, or other
presentations at any time derived or developed by GSK in connection with the
Products.
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2.06 Right of First Refusal to Purchase Products.
(a) Subject to the terms and conditions of this Agreement, in the event
that at any time during the Term GSK decides to divest itself of any of the
Products, whether by assignment, sale, conveyance, transfer, license or other
means, GSK will first offer to Celgene the opportunity to purchase all the
Products. Without limiting the generality of the foregoing, GSK will refrain
from offering any of the Products to any third Party until either (a) Celgene
has advised GSK in writing that it elects not to accept GSK's offer of the
Products, or (b) following a period of good faith negotiation, GSK and Celgene
are unable to reach an agreement concerning a purchase of the Products.
Whereupon, GSK may offer and sell any of the Products to a Third Party on terms
no less favorable to GSK than those last offered by GSK to Celgene, it being
understood, however, that any such sale to a Third Party that occurs prior to
the expiration of the Term shall be subject to Celgene's rights under this
Agreement, including Celgene's right to act as exclusive distributor of the
Products in the Territory. If GSK does not complete such sale to a Third Party
within one hundred eighty (180) days after either date described in the
immediately preceding sentence, GSK shall again be subject to the provisions of
this Section 2.06 with respect to any divestiture of the Products.
(b) In the event that at any time after the expiration or termination
of the Term and within twenty-four (24) months after such expiration or
termination GSK decides to divest itself of any of the Products, whether by
assignment, sale, conveyance, transfer, license or other means, GSK will afford
Celgene an opportunity to purchase such Products; it being understood, however,
that such opportunity shall not constitute a right of first refusal.
(c) The completion of any assignment, sale, conveyance, transfer,
license and delivery with respect to the Products pursuant to this Section 2.06
shall be referred to herein as the "Transfer" of the Products. The Parties
acknowledge that the completion of the Transfer may be subject to governmental
consents or approvals, including but not limited to approval of the Transfer
under the Hart-Scott-Rodino Anti-Trust Improvement Act of 1976, as amended.
(d) In the event that at any time within twenty-four (24) months after
the termination or expiration of this Agreement, GSK decides to abandon one or
more of the Products, GSK will first offer to Celgene the opportunity to acquire
the rights to such Products. Pursuant to such offer, GSK and Celgene shall
conduct good faith negotiations with respect to the terms of such acquisition.
2.07 Non-Compete. During the Term of this Agreement, Celgene shall not
distribute, market, promote, detail, advertise or sell any product within the
same therapeutic category, containing the same active pharmaceutical ingredient
and approved for the same indication that competes directly with any Product.
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ARTICLE 3
CELGENE RESPONSIBILITIES
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3.01 Distribution Diligence. In fulfillment of its obligations under
this Agreement, during the Term Celgene shall:
(i) maintain levels of inventory, after the Transition Period, of
each of the Products no greater than is reasonable and
consistent with customary industry practice and Celgene's
historical sales patterns of the products to its customers;
(ii) provide, at its expense, a traceability system for the
Products reasonably comparable to customary industry
practices;
(iii) use Commercially Reasonable Efforts to ensure that all sales
force personnel promote the Products in a manner that is
consistent with the Products' applicable Product Registration
and labeling and that is permitted by Applicable Laws. If
Celgene becomes aware of any such activity in contravention of
the immediately foregoing standards, Celgene shall take prompt
affirmative action to ensure that such activity shall cease,
and take additional remedial action to advise its sales
personnel concerning the activities described in this
subsection;
(iv) use Commercially Reasonable Efforts not to take any action
which constitutes a violation of Applicable Laws or breach of
this Agreement and would have a material adverse impact on:
(a) the commercialization of the Products in the
Territory; or
(b) the then existing business of GSK, its Affiliates and
licensees with respect to the Products outside of the
Territory;
(v) obtain, as soon as reasonably practicable following the
Effective Date, and no later than six (6) months following the
Effective Date, at Celgene's sole and exclusive expense, any
and all requisite NDCs in Celgene's name for the Products,
and, except as otherwise provided in this Agreement, obtain
any and all governmental approvals as are required for Celgene
to fulfill its obligations hereunder. GSK shall cause the NDC
number obtained by Celgene to appear on all Products (other
than Products consisting of current inventory of finished
goods) sold by GSK to Celgene as soon as reasonably
practicable;
(vi) maintain the availability of the current package inserts with
respect to the Products on any website maintained by Celgene
or its Affiliates for the distribution, marketing, promotion,
detailing, advertising or sale of the Products and at such
other locations where Celgene or any such Affiliates make
information regarding the Products available; and
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(vii) use Commercially Reasonable Efforts to sell, market, detail,
promote, advertise and distribute the Products in a manner
that will not have a material adverse effect on the Products.
(viii) include all Products in its Patient Assistance Program. For
purposes of this clause (viii), the "Patient Assistance
Program" shall be those indigent programs maintained by
Celgene.
3.02 Promotional Materials and Activities
(a) Subject to the provisions of Section 3.02(b) below, Celgene shall
be solely responsible, at its sole expense and under its sole control for
conducting all promotional activities and for designing, preparing and
distributing all materials, advertisements and activities used in the promotion,
advertising and marketing of the Products within the Territory. Celgene shall
ensure that all materials, advertisements and promotional activities comply
with, and Celgene shall be solely responsible and liable for any failure of such
materials and activities to comply with, the applicable labeling and Product
Registration for any of the Products and with Applicable Laws and regulations,
notwithstanding any prior review or approval of such materials or activities by
GSK and notwithstanding that such materials or activities may have been
previously reviewed, used or conducted by GSK. Celgene shall be solely
responsible for fulfilling regulatory requirements pertaining to its promotional
materials and activities, including, without limitation, sole responsibility for
submitting to FDA all promotional and advertising materials prepared by or for
Celgene at the time of initial dissemination, by way of a Form FDA-2253,
consistent with 21 CFR Part 314.81. To this effect, GSK shall, upon the
Effective Date, or as soon thereafter as is reasonably practicable, place a
letter on file with DDMAC with respect to the Products advising DDMAC that
Celgene shall be the sole marketer and promoter of the Products in the Territory
and requesting that DDMAC address regulatory inquiries and concerns regarding
Celgene's promotional activities solely with Celgene. Celgene shall promptly,
but in no event less than one (1) Business Day after Celgene's receipt thereof,
provide a copy to GSK of any correspondence from a government agency with
respect to any of the Products, including, but not limited to, the FDA,
reflecting any purported legal or regulatory violations or legal or regulatory
action being considered or taken by such government agency, including without
limitation, copies of FDA NOV's and Warning Letters. Unless otherwise required,
Celgene shall not provide GSK with copies of any promotional materials or
advertising or notify GSK of any promotional activities unless pursuant to a
written request by GSK. Celgene shall absorb and be solely responsible for any
and all lost profits, lost revenues, damages, losses, expenses and costs
incurred by Celgene, its Affiliates, and any CSO retained by Celgene pursuant to
the terms of this Agreement, arising from the failure of any promotional
materials or advertising used, or activities conducted by, Celgene to comply
with the applicable labeling, the Product Registrations and/or with Applicable
Laws. Without limiting the rights GSK may have under the indemnification
provisions of this Agreement, Celgene shall promptly reimburse GSK and its
Affiliates for any and all damages, losses, expenses and costs suffered or
incurred by GSK and its Affiliates arising from (i) the failure of any
promotional materials or advertising used or activities conducted by Celgene to
comply with the applicable labeling, the applicable Product Registrations,
Applicable Laws, and/or any comments, guidance or direction given by FDA or
DDMAC in the Pre-Clearance Process pursuant to Section 3.02(b)(ii) or (ii) the
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failure of Celgene or its representatives or any CSO selected pursuant to the
terms of this Agreement to promote the Products in compliance with the
applicable labeling, the applicable Product Registrations and/or with Applicable
Laws. GSK shall use Commercially Reasonable Efforts to mitigate or limit its
losses, expenses and costs incurred in connection with any matter described in
(i) or (ii) above and for purposes of the preceding sentence, it is understood
and agreed that the losses, expenses and costs incurred by GSK shall include,
without limitation, the losses, expenses and costs incurred by GSK to so
mitigate or limit the effect or impact of (i) or (ii) above, on GSK and its
Affiliates products or corporate image (including, but not limited to, the costs
of any remedial action undertaken by GSK to communicate with physicians or
customers (including, but not limited to so-called "dear doctor letters").
(b)(i) If Celgene (or GSK) shall receive a Warning Letter from FDA
which relates to marketing, promotion, advertisement, sale
or distribution of the Products after the Effective Date,
or Celgene (or GSK) shall receive two (2) NOV's from the
FDA which relate to marketing, promotion, advertisement,
sale or distribution of the Products after the Effective
Date, GSK shall have the right to call, and Celgene shall
participate/or attend at its own expense, a meeting of
Celgene (which shall include senior level marketing and
sales management of Celgene) and GSK, to be held in
Research Triangle Park, N.C. The purpose of such meeting
shall be to discuss the promotional pieces or practices
which led to the issuance of the Warning Letter or the
NOV's, as the case may be, and to discuss, if appropriate,
appropriate corrective or remedial measures to Celgene's
promotional review process. Subsequent to any such meeting
or in lieu of such meeting (if such meeting is not held as
a result of the mutual agreement of the Parties or as a
result of Celgene's failure or refusal to attend), GSK may,
in its sole and absolute discretion, at any time after the
issuance of a Warning Letter or a second NOV from FDA
related to the Products after the Effective Date, decide to
invoke the promotional review procedures set forth in
Section 3.02(b)(ii) below by sending written notice thereof
to Celgene (hereinafter, a "Promotional Review Notice").
(ii) In the event that GSK sends a Promotional Review Notice to
Celgene, Celgene shall comply with the procedures set forth
in this Section 3.02(b)(ii). Celgene shall ensure that all
marketing and advertising materials and activities comply
with the applicable labeling and the applicable Product
Registration for any of the Products and with Applicable
Laws, including, without limitation, addressing any
concerns which were the subject of such FDA letter(s). For
a period of twelve (12) months after the Promotional Review
Notice (the "Pre-Clearance Period"), Celgene shall submit
all of the following for review and approval by DDMAC (the
"Pre-Clearance Process") prior to use or dissemination; any
and all marketing, advertising, promotional and related
materials and activities (including, without limitation,
detail aids, letters, brochures, reprints and other printed
materials shown to or left with healthcare providers,
letters, brochures and other printed materials intended for
consumers, website content, materials for use in
promotional programs, and any print, television, radio, and
other media advertising materials intended for healthcare
providers or consumers), labeling, press materials, updates
and corrections to the Physicians Desk Reference with
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respect to the Products, speaker training materials
(including slides and slide kits), sales training materials
and other materials and communications originating from
home offices, regional offices, local offices or hub
offices and sent to the sales force regarding promotional
messages or strategies for the Products. Celgene shall not
use any materials or make any claims in advertising,
promoting or selling the Products which have not gone
through the Pre-Clearance Process and received specific and
entire written approval by DDMAC; provided, however, that
in the case of materials not accepted for review by DDMAC,
Celgene shall ensure that all such materials and the claims
and promotional messages therein; (a) are consistent with
the materials and claims that have gone through the
Pre-Clearance Process and received written approval by
DDMAC and (b) comply with all comments, direction and
guidance given by DDMAC during the Pre-Clearance Period.
Celgene shall ensure that all promotional programs and
activities of all sales representatives promoting the
Products comply with any and all comments, direction or
guidance given by DDMAC during the Pre-Clearance Period.
Upon expiration of the Pre-Clearance Period, Celgene shall
continue to promote, detail, sell and advertise the
Products in a manner consistent with, and in full
compliance with, all comments, directions and guidance
received from DDMAC. Celgene shall be solely responsible
for submitting all promotional and advertising materials
prepared by or for it to the FDA by way of a Form 2253 or
otherwise. GSK shall have the right to immediately
terminate this Agreement if; (i) Celgene shall fail to
fully comply with the requirements of this Section
3.02(b)(ii) or (iii) FDA issues a Warning Letter or NOV
with respect to any of the Products at any time during or
after the Pre-Clearance Period.
(c) Celgene acknowledges that GSK has advised Celgene that GSK is not
currently actively promoting any of the Products in the Territory and has not
done so for several years, and that GSK does not have current materials designed
for advertising or promoting the Products in the Territory. GSK shall provide
Celgene with copies of any advertising, promotional or training materials in its
possession and previously used by GSK relating to the Products, and shall permit
Celgene, subject to compliance by Celgene with Applicable Laws, to update, adapt
and use such materials in the Territory in developing new promotional materials
(subject to any copyrights or other rights reserved to GSK, its Affiliates and
to Third Parties in such materials). GSK reserves and retains title and all
rights, including copyright rights, in and to all written, visual and electronic
works and other materials (including without limitation training materials,
promotion materials, brochures and other detail literature) provided by it to
Celgene under this Agreement. Subject to the foregoing, Celgene is granted the
nonexclusive right under this Section to use, copy, modify, and distribute such
materials only for the purposes of this Agreement and in furtherance of the
rights granted to Celgene hereunder, for the Term for any of the Products to
which such works and materials relate. Celgene shall ensure that all copyright
notices and this permission notice appear on all copies of the written materials
provided by GSK and all adaptations and derivative works thereof. Any and all
new promotional material developed by Celgene, including that which adapts or
utilizes materials supplied to Celgene by GSK, shall be filed with FDA at the
time of initial dissemination via Form FDA-2253.
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(d) Celgene shall have strategic responsibility and sole authority and
responsibility, at its sole expense, for conducting independent and
non-independent symposia, speaker training and engagement programs, advisory
board meetings and other consulting arrangements, scientific exhibits and other
types of scientific exchange, and other such events or programs as Celgene, in
its sole discretion, deems to be appropriate with respect to the Products within
the Territory; provided, however, that any and all such events and programs must
comply in all respects with Applicable Laws and relevant FDA policies, including
without limitation, the FDA's Guidance on Industry-Supported Educational and
Scientific Activities.
3.03 Use of Trademarks; Trade Dress. During the Term of this Agreement,
and subject to the terms and conditions of this Agreement:
(a) Celgene shall use the Trademarks, on an exclusive royalty-free
basis, to promote, market, sell and distribute the Products within the
Territory. Celgene shall not identify the Products by any designation other than
the Trademarks for the Products. With respect to all Products which bear
Celgene's NDC codes as provided herein, Celgene shall be identified as the
distributor of such Products on the Products' label as the same may be required
and specified under Applicable Law, or if Applicable Law does not specify how
the distributor shall be indicated on a Products' label, then as determined
(including without limitation as to size and placement) jointly by GSK and
Celgene. The use of the Trademarks by Celgene shall be expressly subject to
subparagraph (c) below.
(b) Celgene undertakes to use the Trademarks only in respect of the
Products purchased from GSK or its designee pursuant hereto, only in accordance
with the standards of quality established or approved by GSK or its designee,
and only in the Territory. Celgene shall permit duly authorized representatives
of GSK to inspect, on the premises of Celgene or its subcontractors and agents,
at reasonable times during normal business hours and upon not less than ten (10)
Business Days prior written notice, inventory of the Products, Celgene's quality
control records, and Celgene's facilities used in or relating to the storage,
distribution or sale of the Products to ensure compliance with quality control
standards and with applicable terms of this Agreement pertaining to the use of
the Trademarks.
(c) Whenever Celgene uses the Trademarks in advertising or in any other
manner in connection with the Products, Celgene shall clearly indicate that the
Trademarks are owned by the GlaxoSmithKline group of companies. When using the
Trademarks under this Agreement, Celgene shall comply with all Applicable Laws
pertaining to the Trademarks in force at any time in the Territory. During the
Term of this Agreement, Celgene shall provide GSK with copies of such foregoing
material on a periodic basis, as requested by GSK, for approval of the use of
the Trademarks by Celgene. Celgene shall promptly take any and all actions
directed by GSK with respect to Celgene's use of the Trademarks that are
reasonably designed to ensure compliance with the provisions of this Section
3.03.
(d) Celgene acknowledges and agrees that GSK and/or its Affiliates, is,
and will remain the owner of the Trademarks. Celgene shall not at any time do,
cause to be done, or permit any of its employees, agents, contractors and
subcontractors to commit any act inconsistent with, contesting or in any way
impairing, or tending to impair, such ownership.
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Celgene agrees that all use of the Trademarks by Celgene shall inure to the
benefit of and be on behalf of GSK or its Affiliates. Celgene acknowledges that
nothing in this Agreement shall give Celgene any right, title or interest in the
Trademarks other than the right to use the Trademarks within the Territory in
accordance with this Agreement. Celgene agrees that it will not challenge GSK's
or its Affiliates' title to, or ownership of, the Trademarks, or attack or
contest the validity of the Trademarks. All goodwill accruing to the Trademarks
as a result of the use of the Trademarks in the performance of this Agreement
shall belong solely to GSK or its Affiliates. In the event that Celgene acquires
any rights in the Trademarks in connection with Celgene's activities pursuant to
this Agreement, Celgene shall assign, and hereby does assign, to GSK or its
Affiliates all such rights, including any related goodwill.
(e) Celgene is limited to using the Trademarks in connection with the
Internet as follows:
(i) the use must be in compliance with local rules regarding
advertising of pharmaceuticals on the Internet;
(ii) the use of any Trademarks as a domain name is limited to the
relevant country code domain within the Territory. No
license is granted to use the ".com generic code domain" or
any other such top-level domain. All domain names containing
the Trademark shall be registered and maintained by and in
the name of GSK or its designee;
(iii) the use of any Trademarks as a domain name is limited to use
on websites with universal resource locaters using the
relevant country code domain within the Territory and aimed
at audiences in those countries in the Territory;
(iv) appropriate disclaimers must be included in any website to
the effect that it is intended for residents in that country
within the Territory only;
(v) in using any of the Trademarks as a domain name or on the
Internet, Celgene will not have and shall not represent in
any way that it has any title or right to the ownership or
registration or their use, except as provided in this
Agreement. Celgene will at all times indicate that each of
the Trademarks is a trademark of GSK used under license.
3.04 Trademark Infringement by Third Parties. If either Party becomes
aware that a Third Party is infringing any Trademark used in connection with the
Products, such Party shall give written notice to the other Party describing in
detail the nature of such infringement. GSK and its Affiliates shall have the
sole right, but not the obligation, to enforce any such Trademarks against such
Third Party infringer to the extent deemed necessary or appropriate by GSK or
its Affiliates, in their reasonable discretion, and to settle or compromise any
such possible infringement by taking such action as GSK or its Affiliates may
determine in their sole and absolute discretion; provided, however, that GSK
shall not settle any such potential infringement in a manner that materially
adversely affects the rights granted to Celgene hereunder, except with
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Celgene's prior written consent (which consent shall not be unreasonably
withheld). Celgene shall provide GSK all reasonable assistance (including,
without limitation, making documents and records available for review and
copying, and making persons within its control available for pertinent
testimony), at GSK's expense, in such enforcement.
3.05 Rebates. Celgene shall process, administer and be financially
responsible for all rebates pursuant to any government rebate programs and all
commercial rebates, with respect to government claims for the Products.
3.06 Medicaid Information. With respect to any of the Products sold by
Celgene after the Effective Date which bears an NDC number of GSK or any of
GSK's Affiliates, Celgene shall deliver to GSK (and to the extent necessary for
Celgene to comply with its Health Care Financing Administration reporting
obligations, GSK shall deliver to Celgene), within fifteen (15) days after the
end of each Calendar Quarter, the following information: (a) the "best price"
(as defined under the Social Security Act, 42 USC ss. 1396r-8(c)(1)(C)) for each
of such Products, identified by NDC number, and (b) the "average manufacturer
price" (as defined under the Social Security Act, 42 USC ss. 1396r-8(k)(1)) and
the sales dollar amount as well as the number of units for each of such
Products, each identified by NDC number. Celgene agrees to provide to GSK any
additional data or other information required for the calculation of the rebates
contemplated in Section 3.05. Each party agrees that the other party may use all
information described in this Section 3.06 in reporting to the Centers for
Medicaid and Medicare Services.
3.07 Federal Government Pricing Programs. Promptly after the Effective
Date, GSK shall notify the Health Care Financing Administration, the United
States Department of Defense, the Office of Drug Pricing and the Veteran's
Affairs National Acquisition Center (the foregoing being hereinafter
collectively referred to as the "Federal Programs") of Celgene's distribution
rights with respect to the Products, and that as of the Effective Date that GSK
will no longer support or sell the Products under any contracts in place with
said Federal Programs. Celgene shall establish its own contractual relationships
with the Federal Programs as soon as commercially reasonable.
3.08 Shipping and Distribution Obligations.
(a) During the Transition Period. From and after the Effective Date,
GSK shall perform the following services for Celgene with respect to the
Products: (i) GSK shall process orders for Celgene for the first three (3)
months of the Transition Period; provided, however, that Celgene receives all
purchase orders from customers and that all invoicing of customers shall be done
by Celgene; and (ii) GSK shall warehouse and ship the Products during the
Transition Period, but only as to those customers that were GSK customers prior
to the Effective Date of this Agreement. Celgene may, at its sole discretion,
terminate the Transition Period at any time before the date that is nine (9)
months after the Effective Date by providing written notice to GSK within
fifteen (15) Business Days prior to such early termination of the Transition
Period. For purposes of this Section 3.08, "GSK customers" shall mean those
customers to whom GSK previously shipped Products prior to the Effective Date.
GSK agrees and confirms that no Products will be shipped, sold, distributed or
released during the Transition Period prior to receipt of a certificate of
analysis for said Products as required under Section 6.02 hereinbelow.
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The services to be provided by GSK pursuant to this Section 3.08(a) shall be at
its sole cost and expense, it being understood and agreed, however, that the
price for Products during the Transition Period reflects an amount intended to
compensate GSK in full for such services.
(b) From and after the expiration of the Transition Period. From and
after the expiration of the Transition Period, Celgene shall: (A) ship and
distribute the Products to its customers; and (B) warehouse the Products.
Celgene agrees and confirms that no Products will be shipped, sold, distributed
or released after the Transition Period prior to receipt of a certificate of
analysis for said Products as required under Section 6.02 hereinbelow.
(c) From and after the Effective Date. Commencing on the Effective Date
and thereafter, Celgene shall: (i) invoice and bill the purchasers of the
Products from Celgene; (ii) confirm all orders placed with Celgene in accordance
with Celgene's customary practices; and (iii) collect the receivables resulting
from Celgene's sales of Products.
3.09 Pricing. From and after the Effective Date, Celgene shall have the
sole authority to determine the prices of Products sold by it during the Term
and to establish its own pricing policy for the Products within the Territory,
including price increases or decreases and the timing thereof as determined by
Celgene. Celgene will provide GSK not less than five (5) Business Days' notice
to GSK of any such price changes.
3.10 Sales Force.
(a) Celgene shall be solely responsible for the costs and expenses of
establishing and maintaining its sales force and marketing functions for the
Products, and for conducting its other activities under this Agreement, and ,
subject to the foregoing, shall have the sole authority to control its sales
force and direct the activities of its sales force.
(b) All members of Celgene's sales force (including management and
representatives), and CSO sales force personnel, if any, shall complete a
Product-related training program conducted by Celgene at its cost and expense.
All members of Celgene's sales force (including management and representatives)
and CSO sales force personnel, if any, must pass a competency test with respect
to the Products with a score of ninety percent (90%) or higher. In connection
with Celgene's Product-related training program, GSK shall, to the extent
available and in GSK's possession provide Celgene with copies of any training
materials previously used in training sales representatives in the Territory on
Alkeran Products. Celgene shall have the sole responsibility for any such
materials and for preparing additional and new materials for the Products for
sales training purposes as needed. Ongoing training of Celgene's sales
representatives and other personnel shall be the responsibility of Celgene at
its cost and expense. The contents of any training provided by Celgene that
relates to the Products shall be developed and coordinated by Celgene, and
Celgene shall be solely responsible for training its sales force (including
management and sales representatives) and CSO sales force personnel, if any,
with regard to Applicable Laws and directing such sales force and sales force
personnel to be compliant with Applicable Laws, regardless of whether Celgene
utilized GSK provided materials for training.
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ARTICLE 4
GSK RESPONSIBILITIES
--------------------
4.01 Supply of Products. In order to ensure the quality of the Products
to be sold by Celgene under the Trademarks, Celgene shall purchase exclusively
from GSK, and GSK shall supply exclusively to Celgene, pursuant to Articles 5
and 6 hereof and subject to the other terms and conditions as set forth in this
Agreement, Celgene's entire requirements of Products for marketing, sale and
distribution by Celgene in the Territory during the Term.
4.02 Retention of Product Registrations. During the Term,
(a) GSK shall have sole responsibility for maintaining, and shall
maintain, the Product Registration in the Territory at its expense, including
without limitation filing NDA Annual Reports and paying all user fees, product
fees and establishment fees associated with the Product Registrations in the
Territory. GSK shall keep Celgene informed on a timely basis as to any
developments that would have a material adverse effect on a Product
Registration. Celgene shall cooperate with GSK with respect to obtaining and
maintaining the Product Registrations, and shall execute, acknowledge and
deliver such further instruments at GSK's request and expense, and use
Commercially Reasonable Efforts to do all such other acts, as promptly as
possible, which may be necessary or appropriate to obtain and maintain the
Product Registrations in the Territory. Celgene shall, on a timely basis,
provide to GSK all information that Celgene has from time to time during the
Term for each of the Products that is reasonably necessary and relevant to GSK's
obligations hereunder to fulfill such Product Registration maintenance
requirements (including, but not limited to, providing sales distribution
information concerning the Products). GSK shall have the final decision-making
authority in every case on whether and how to supplement, amend or otherwise
alter the Product Registrations and any other issues in connection with such
Product Registrations (including, but not limited to, decisions, subject to
Section 6.07, to recall the Products) and on whether and how to communicate with
the FDA and other applicable governmental agencies or authorities in connection
with such Product Registrations.
(b) GSK and Celgene each shall make its facilities available at
reasonable times during business hours for inspection by representatives of
governmental agencies. GSK and Celgene each shall notify the other within
twenty-four (24) hours (or, if such twenty-four (24) hour period ends on a day
that is not a Business Day, then prior to Noon on the next following Business
Day) of receipt, and provide a copy thereof, of any notice of any FDA or other
governmental agency inspection, investigation or other inquiry, or other
material governmental notice or communication, relating to the manufacture,
sale, marketing, promotion, distribution, or use of the Products within the
Territory. Celgene and GSK shall cooperate with each other during any such
inspection, investigation or other inquiry. Celgene and GSK shall discuss any
response to observations or notifications received in connection with any such
inspection, investigation or other inquiry and each shall give the other an
opportunity to comment upon any proposed response before it is made; provided,
however, that (i) GSK will not be required to discuss with Celgene any issues
specific to the manufacture of the Products, or to obtain the consent or
agreement of Celgene with respect to issues related thereto; provided, however,
that
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GSK shall notify Celgene of any issues specific to the manufacture of the
Products that (A) could reasonably be expected, in GSK's discretion, to have a
material affect on Celgene's ability to distribute Products in the Territory,
and (B) have regulatory implications that could reasonably be expected, in GSK's
discretion, have a material affect on Celgene's ability to distribute Products
in the Territory, and (ii) Celgene shall be solely responsible for responding to
regulatory inquiries and actions from government agencies relating to
promotional activities and materials as contemplated by Section 3.02. In the
event of disagreement concerning the form or content of such response, however,
GSK shall be responsible for deciding the appropriate form and content of any
response with respect to any of its governmental agency cited activities and
Celgene shall be responsible for deciding the appropriate form and content of
any response with respect to any of its governmental agency cited activities.
Celgene and GSK will provide each other with copies of all correspondence
received by it from, or filed by it with, any federal, state or local regulatory
authority to the extent pertaining to each of the Products or its , labeling,
packaging, distribution, promotion, advertisement, marketing or sale in the
Territory; provided, however, that Celgene shall not provide copies of
promotional materials or advertising of the Products to GSK unless requested by
GSK in writing. In addition, GSK will provide Celgene copies of all material
correspondence received by GSK from, or filed by GSK with, any federal, state or
local regulatory authority to the extent such correspondence or filing could
reasonably, in GSK's opinion, have an affect on Celgene's ability to perform its
obligations under this Agreement. Nothing in this Section 4.02(b) shall limit or
condition the rights of either Party under Section 6.12.
(c) GSK shall have sole responsibility and authority for, and control
of, all package inserts and package labeling (and any changes or supplements
thereto) for Products, and shall have the responsibility at its expense for
securing any approvals required by FDA to any such changes or supplements
thereto. Celgene shall not at any time do, and neither shall Celgene permit its
agents or representatives to do, any act in violation of the Product
Registration for the Products in the Territory. In the event that any filings
are required to be made with or approvals required to be obtained from
applicable regulatory authorities in order to change or supplement the package
inserts and labeling, GSK shall have the sole responsibility for and authority
to effect such filings and the sole right and discretion on how to effect such
changes at GSK's expense. GSK shall promptly advise Celgene in writing of any
changes or supplements to the package inserts and package labeling for Products.
The Parties acknowledge and agree that all Products sold after the Effective
Date will be sold under a GSK label, and, as soon as reasonably practicable
following the Effective Date, all Products will be identified as GSK products
with Celgene identified as the distributor thereof, including the Celgene logo.
4.03 Prosecution and Maintenance of Trademarks and Patents. During the
applicable Term of this Agreement,
(a) GSK shall register and maintain, or cause to be registered and
maintained, at its cost and expense, the Trademarks in the Territory during the
applicable Term of this Agreement. The rights of the Parties with respect to
Trademark infringement are set forth in Section 3.04 of this Agreement.
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(b) Notwithstanding any other provision of this Agreement to the
contrary, GSK and its Affiliates shall have the sole right, but not the
obligation, at their reasonable discretion and at their sole expense, to
prosecute, maintain, enforce, defend or abandon any patent rights and know-how
owned or controlled by GSK covering the manufacture of Products. GSK shall not
abandon any patent right or know-how owned or controlled by GSK with respect to
the Products in the Territory without giving sixty (60) days prior written
notice to Celgene and permitting Celgene at its sole and exclusive expense to
take reasonable and customary actions to maintain or preserve such patent rights
or know-how. In the event that GSK shall, in its discretion, elect not to defend
any patent rights with respect to Products controlled by GSK in the Territory,
GSK shall provide timely notice of such election to Celgene and give Celgene the
opportunity to defend such patents for the Products at Celgene's sole and
exclusive expense, and GSK will provide reasonable cooperation and assistance to
Celgene in such defense.
(c) GSK shall have the sole right, but not the obligation, at its sole
discretion and expense, to maintain and enforce any contract entered into by GSK
covering the supply of any compounds, intermediates, biomaterials, packaging
components, containers and other materials used in the manufacture of a Product.
4.04 No Obligation to Develop New Formulations or Indications. GSK
shall have no obligation, express or implied, to develop new formulations,
indications, dosages, presentations, forms of administration, or preparations
for Products.
ARTICLE 5
PURCHASE AND SALE OF PRODUCTS
5.01 Purchase of Products - Annual Minimum Purchase Requirements.
(a) Purchase of Products. Subject to the terms and conditions of this
Agreement, GSK agrees to supply and sell to Celgene, and Celgene agrees to
purchase from GSK, Celgene's entire requirements of the Products in dosage form
and packaged in the manner described in EXHIBIT 5.01 hereto during the Term of
this Agreement at the applicable transfer prices specified in Section 5.05.
Products sold by GSK under this Agreement shall have a minimum of a twelve (12)
month shelf life remaining on the Products as of the delivery date to Celgene.
(b) Annual Minimum Purchase Requirements. Celgene acknowledges and
agrees that it shall purchase from GSK in each Annual Period during the Term
Products in the aggregate total dollar amounts as follows (each an "Annual
Minimum Purchase Requirement", collectively the "Annual Minimum Purchase
Requirements").
---------------------------------------------------------------
ANNUAL MINIMUM PURCHASE
ANNUAL PERIOD REQUIREMENT
---------------------------------------------------------------
4/1/03 - 12/31/03 $13,125,000
---------------------------------------------------------------
1/1/04 - 12/31/04 $18,500,000
---------------------------------------------------------------
1/1/05- 12/31/05 $20,000,000
---------------------------------------------------------------
1/1/06 - 3/31/06* $5,000,000
---------------------------------------------------------------
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*In the event that this Agreement is extended, the Annual Minimum Purchase
Requirement for each subsequent Annual Period shall be mutually agreed upon in
writing by the Parties.
Notwithstanding anything to the contrary in this Agreement, the Annual Minimum
Purchase Requirement shall be subject to adjustment as follows:
(i) If the FDA approves for marketing, a generic version of any of the
Products, then, at Celgene's request from time to time (but not more
frequently than twice per twelve (12) month period), the Parties shall
negotiate in good faith a reduction of the Annual Minimum Purchase
Requirement for the Annual Period during which such generic version
becomes commercially available and each subsequent Annual Period in
order to provide relief to Celegene with respect to the anticipated
impact of such generic version on the Products' market share and/or Net
Wholesale Price. Should the Parties fail to reach agreement with
respect to such adjustment, Celgene shall be entitled to terminate this
Agreement immediately upon the delivery of written notice to GSK in
accordance with Section 12.02 hereof. Each Party shall promptly inform
the other Party if it becomes aware of FDA approval of a generic
version of any of the Products or of other events indicating that such
approval is reasonably likely to occur.
(ii) If GSK, for any reason, fails to timely ship to Celgene conforming
Products ordered by Celgene, and notwithstanding that such failure may
be excused in whole or in part pursuant to the terms of Sections
5.02(b), 5.03(d), or 10.01, or that such failure is otherwise governed
by any other provision of this Agreement, including Sections 5.10 or
6.03, the amount that would have been invoiced to Celgene by GSK in
respect of the conforming Products that GSK failed to timely ship shall
be deemed a credit against the Annual Minimum Purchase Requirement for
such Annual Period;
(iii) If there shall be a Recall of any of the Products during the
Term, the Annual Minimum Purchase Requirement for the Annual Period
during which such Recall occurs shall be reduced by the value (based on
the Net Wholesale Price) of the lots affected by such Recall; and
(iv) If this Agreement shall be terminated prior to the expiration of
the Term, the Annual Minimum Purchase Requirement for the Annual Period
during which such recall occurs shall be prorated accordingly.
5.02 Semi-Annual Supply Schedule; Purchase Orders.
(a) Within thirty (30) days after the Effective Date, Celgene shall
deliver to GSK the following:
(i) a Purchase Order covering all of Celgene's requirements of
the Products (by month) for the twelve (12) month period
ending March 31, 2004. It is understood and agreed that (A)
Products subject to such Purchase Order shall be (x)
shipped during the Transition Period in accordance with
Section 3.08(a), and (y) invoiced by GSK to Celgene during
the Transition Period
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and thereafter in accordance with Section 5.07(a); (B) the
Existing Inventory to be delivered to Celgene following the
end of the Transition Period shall be deemed to be a
shipment against such Purchase Order; and (C) the Products
required to fill the first six (6) month period of such
Purchase Order will come from GSK inventories on hand as of
the Effective Date; and
(ii) a good faith forecast of Celgene's requirements of the
Products (by quarter) for the twelve (12) month period
commencing April 1, 2004 and ending March 31, 2005.
(b) No later than October 1, 2003 and each succeeding April 1 and
October 1 during the Term, Celgene shall deliver to GSK the following:
(i) a Purchase Order covering all of Celgene's requirements of
the Products (by month) for the six (6) month period
commencing six (6) months after the date of the Purchase
Order (i.e., a Purchase Order issued on October 1 would
cover the six (6) months period commencing on the following
April 1 and a Purchase Order issued on April 1 would cover
the six (6) month period commencing on the following
October 1); and
(ii) a good faith forecast of Celgene's requirements of the
Products (by quarter) for the twelve (12) month period
commencing twelve (12) months after the date of the
forecast (e.g., the October 1, 2003 forecast would cover
the twelve (12) month period commencing October 1, 2004).
(c) Any twelve (12) month forecast, whether pursuant to Section
5.02(a)(ii) or Section 5.02(b)(ii), is hereinafter referred to as a "Semi-Annual
Supply Schedule." Reference is made to EXHIBIT 5.02(c) hereto which is intended
as a graphic representation of the Semi-Annual Supply Schedule procedures
provided for in this Section 5.02.
(d) A Purchase Order that covers a period that was previously
forecasted by Celgene in a Semi-Annual Supply Schedule may not differ as to the
quantity by more than fifty percent (50%) from the quantity previously
forecasted for such period.
(e) A forecast by Celgene that covers a period that was previously
forecasted by Celgene in a Semi-Annual Supply Schedule may not differ as to
quantity by more than twenty-five percent (25%) from the quantity previously
forecasted for such period.
(f) Notwithstanding anything to the contrary in this Section 5.02, no
Purchase Order or forecast will be required hereunder with respect to any period
of time that would occur after the anticipated expiration or termination of this
Agreement.
(g) In the event that at any time during the Term, GSK's available
supply of the Products is insufficient to fully supply (i) the units of such
Products requested in any outstanding Purchase Orders submitted by Celgene
pursuant to the Semi-Annual Supply Schedule (not
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including excess units ordered by Celgene for which GSK is not obligated to
supply Celgene unless GSK has otherwise accepted the delivery obligations
contained in such order for excess units) and (ii) the requirements of GSK and
its Affiliates for such Products outside the Territory, GSK shall allocate its
available supply of such Products between the units requested in such Celgene
Purchase Orders and the requirements of GSK and its Affiliates outside the
Territory so that Celgene receives at a minimum a pro rata portion of the
available supply determined based on the relative sales of such Products by
Celgene in the Territory and by GSK and its Affiliates outside the Territory
from the Effective Date through the end of the Calendar Quarter immediately
preceding the Calendar Quarter during which such supply shortage occurs.
5.03 Semi-Annual Supply Schedule Authorization and Purchase Order Terms.
(a) Each Semi-Annual Supply Schedule shall be signed by an authorized
representative of Celgene indicating approval of such Semi-Annual Supply
Schedule.
(b) From and after the Transition Period, each Purchase Order shall
specify the date of delivery to Celgene (the "Delivery Date") and the
transportation carrier to be used. If any Purchase Order fails to indicate a
particular transportation carrier to be used for delivery, GSK shall have the
right to select a transportation carrier. In the event that Celgene submits a
Purchase Order which exceeds the quantity of Products specified for the
corresponding period as set forth in the Semi-Annual Supply Schedule or which
changes the Delivery Date specified on a previously submitted Purchase Order for
the same period, GSK will make a good faith effort to supply, but shall have no
obligation to supply to Celgene the amount of any such excess or to allow any
such change in Delivery Date.
(c) Quantities of Products actually shipped by GSK may vary from the
quantities specified in any Purchase Order by up to ten percent (10%) and still
be deemed to be in compliance with such Purchase Order; provided, however, that
Celgene shall only be invoiced for the quantities that GSK actually ships to
Celgene (the "Actual Quantity").
5.04 Order Quantities. Neither a Semi-Annual Supply Schedule forecast
nor a Purchase Order may specify a quantity of Products that is less than the
minimum quantity for such Product set forth on EXHIBIT 5.04 attached hereto;
provided, however, that if the amount specified in a Purchase Order is less than
the minimum quantity but is an amount that is otherwise permitted by Section
5.02(d), the minimum quantity requirement shall not apply to such Purchase
Order.
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5.05 Prices for Products. The prices paid by Celgene to GSK for
Products shall be computed as follows:
(a) With respect to Products invoiced in any Annual Period of the Term,
Celgene shall pay an amount equal to the Applicable Percentage of the Products'
Net Wholesale Price as of the issue date of GSK's invoice to Celgene for the
Products on the aggregate purchases of all Products up to or equal to the Annual
Minimum Purchase Requirement for such Annual Period. The "Applicable Percentage"
shall be eighty-two and one-half percent (82.5%) with respect to Products
invoiced by GSK during the Transition Period and eighty percent (80%) with
respect to Products invoiced by GSK after the Transition Period.
(b) With respect to any Products invoiced in any Annual Period of the
Term in excess of the Annual Minimum Purchase Requirement for such Annual
Period, Celgene shall pay an amount equal to forty percent (40%) of the ordered
Products' Net Wholesale Price as of the issue date of GSK's invoice to Celgene
for such Products.
5.06 Delivery. From and after the end of the Transition Period, GSK
shall ship the Products to Celgene F.O.B. GSK's manufacturing facilities (or
those of its Affiliates or its subcontractors, if any) freight collect and
payable by Celgene, during normal business hours. Celgene shall be responsible
for selecting the carrier to transport Products from the GSK facilities to the
shipping address designated by Celgene. From and after the end of the Transition
Period, the quantities of Products for each calendar month set forth in the
Semi-Annual Supply Schedules shall be delivered within two (2) weeks of the
Delivery Date set forth in the Purchase Order applicable to such quantities,
provided, that GSK shall have no liability for delivery delays caused by any
carrier's failure to meet the delivery times agreed to by such carrier.
Notwithstanding anything herein to the contrary, in the event delivery within
the times specified above will not be possible, GSK may request (in writing or
by electronic mail) an alternate Delivery Date and Celgene shall not
unreasonably withhold its consent to such alternate Delivery Date (which consent
shall be in writing or by electronic mail); provided, however that the alternate
Delivery Date shall not be more than fifteen (15) days from the original
Delivery Date. From and after the end of the Transition Period, title to and
risk of loss with respect to Products shall pass from GSK to Celgene upon
delivery of the Products to the carrier and Celgene shall be responsible for
procuring insurance for the transport of the Products from the GSK facilities to
the shipping address designated by Celgene.
5.07 Invoicing; Payment.
(a) All Products manufactured under this Agreement shall be invoiced by
GSK to Celgene (i) during the Transition Period, upon shipment to a customer
pursuant to Section 3.08(a), and (ii) after the Transition Period, upon shipment
thereof to Celgene. Celgene shall be responsible for all freight and insurance,
and all sales, use, excise and other taxes and duties imposed by any
Governmental Authority (including, without limitation, any taxes imposed with
respect to the Products (other than income taxes), the actual amount thereof
shall be included in the applicable invoice, as set forth above and paid by
Celgene) that are applicable to the purchase or shipment of the Products. In the
event GSK initially pays any such freight, insurance, taxes,
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or duties applicable to the purchase or shipment of such Products (all of which
are to be borne by Celgene pursuant to this Agreement), such amounts paid by GSK
shall be invoiced by GSK to Celgene and shall be paid by Celgene in accordance
with Section 5.07(b).
(b) Payments for all amounts invoiced by GSK shall be due and payable
to GSK on or before the thirtieth (30th) day after the date of such invoice, in
accordance with Section 7.01. In the event that any such payment is not received
by GSK on or before the thirtieth (30th) day following the date of the related
invoice, the unpaid portion of such payment shall accrue interest at the rate
specified for late payments in Section 7.04(d) until such unpaid portion is paid
to GSK in full, and Celgene shall be responsible for reasonable attorneys' fees
and expenses incurred by GSK in connection with the collection thereof;
provided, however, that in the event that payment is not received with respect
to two or more consecutive invoices, GSK shall have the right to require payment
in advance for all future orders of Products beginning with the month
immediately following the date of the second (2nd) of such consecutive invoices.
5.08 Subcontracts. GSK may subcontract all or any part of the
manufacture of the Products without the consent of Celgene, provided, however,
that GSK shall remain responsible for all of its obligations to Celgene under
this Agreement, including, without limitation, the performance of its
subcontractors in supplying Products to Celgene. Celgene acknowledges that GSK
is currently subcontracting part or all of the manufacture of the Products to
certain of its Affiliates and subcontractors. EXHIBIT 5.08 sets forth a list of
the current primary subcontractors that manufacture the Products for GSK.
5.09 Forms. In ordering and delivering Products, Celgene and GSK may
use their respective standard forms, provided that nothing in those forms shall
be construed to modify or amend the terms and conditions of this Agreement, and,
in the case of any conflict herewith, the terms and conditions of this Agreement
shall control.
5.10 Quantitative Deficiencies. Celgene shall notify GSK in writing of
any claim relating to quantitative deficiencies from the applicable shipping
documentation in any shipment of Products for which Celgene considers GSK to be
responsible within fifteen (15) days following receipt of any such shipment. Any
claim for a quantitative deficiency from the applicable shipping documentation
that is not made within such fifteen (15) days shall be deemed to have been
waived by Celgene and Celgene shall be obligated to make payment for such
Products in accordance with Sections 5.06, 5.07 and 5.08 above. In the event
Celgene determines there is a quantitative deficiency from the applicable
shipping documentation, the Parties shall investigate such deficiency and, if
the Parties agree that GSK is responsible for such deficiency, the Actual
Quantity shall be adjusted to reflect the Parties' agreement; provided, however,
that GSK shall have the option of rectifying any such deficiency that occurred
prior to shipment by promptly shipping the appropriate quantities of Products,
as the case may be, to Celgene, in which case the Actual Quantity shall be
readjusted to include such shipment. Celgene's exclusive remedy for any
quantitative deficiencies shall be to pay only for actual quantities shipped or,
at GSK's option, receive the appropriate quantities, as provided herein.(1)
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5.11 Delivery of Existing Inventory. Within three (3) Business Days
following the end of the Transition Period (including any early termination
thereof), the Existing Inventory shall be delivered to Celgene F.O.B. GSK's
manufacturing facilities (or those of its Affiliates or subcontractors, if any),
freight collect. Payment for Celgene's purchase of the Existing Inventory shall
be made in accordance with Article 7. All Existing Inventory delivered to
Celgene shall have an expiration date of not less than twelve (12) months from
the date of delivery by GSK.
5.12 DISCLAIMER OF WARRANTIES. EXCEPT AS EXPRESSLY PROVIDED IN THIS
AGREEMENT, THERE ARE NO REPRESENTATIONS OR WARRANTIES, EXPRESS OR IMPLIED, MADE
OR GIVEN BY EITHER PARTY HEREUNDER, INCLUDING, WITHOUT LIMITATION, ANY WARRANTY
OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE OR USE OF ANY PRODUCT.
ARTICLE 6
MANUFACTURE OF PRODUCTS;
CERTAIN REGULATORY MATTERS; COMMUNICATION
-----------------------------------------
6.01 Manufacture of Products. GSK shall manufacture or cause the
Products to be manufactured in accordance with Good Manufacturing Practices,
Applicable Laws, the Manufacturing Documentation and the applicable Product
Registration, as each may be amended from time to time. At the time that GSK
supplies the Products to Celgene, the Products will not be adulterated or
misbranded within the meaning of the Federal Food, Drug and Cosmetic Act.
6.02 Certificate of Analysis. GSK shall provide, or cause to be
provided to Celgene, whichever the case may be, a certificate of analysis for
each shipment of Products, within three (3) Business Days from the date that
such Products are shipped to Celgene.
6.03 Rejection of Products by Celgene; Remedies.
(a) Celgene shall notify GSK of any rejection of any of the Products
within thirty (30) days after delivery of such Products to Celgene and shall set
forth in such notification the basis under this Agreement for such rejection,
including any testing or inspection results; provided, however, in the case of
any of the Products having latent defects, which upon examination in accordance
with Celgene's reasonable testing or inspection procedures could not have been
discovered, Celgene must give notice to GSK within fifteen (15) days after
discovery of such defect, setting forth the basis for such rejection. Failure to
so notify GSK of, or to identify the basis under this Agreement for, rejection
of any of the Products within such fifteen (15) day period shall constitute
acceptance of such Products and, thereafter, Celgene shall be obligated to make
payment for such Products in accordance with Sections 5.05, 5.06 and 5.07 above.
If the Parties disagree as to whether any of the Products conforms with
applicable labeling or the Product Registration for such Product, then samples
and/or batch records, as appropriate, from the batch which is in dispute shall
promptly be submitted for testing and
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evaluation to an independent Third Party as shall be agreed to in writing by
both Parties. The determination of such Third Party as to whether the Products
conform to applicable labeling or the Product Registration for such Products
will be final and binding. Except as provided in Section 6.03(b) below, the cost
of the testing and evaluation by the Third Party shall be borne by (i) Celgene
if the Third Party determines that the Products conform with applicable labeling
and the Product Registration for such Product, and (ii) GSK if the Third Party
determines that the Products do not conform with applicable labeling or the
Product Registration for such Product.
(b) If GSK agrees with Celgene's notification of non-conforming
Products, or GSK fails to contest such notification in writing within ten (10)
days after receipt of such notification, or the Third Party, pursuant to Section
6.03(a) above, concludes that the Products do not conform with the applicable
labeling or the Product Registration for such Products, GSK shall reimburse
Celgene for all reasonable costs and expenses incurred by it in connection with
the non-conforming Products and GSK shall, at Celgene's option, (i) credit
Celgene for the invoiced amount paid by Celgene to GSK for such rejected
Products, or (ii) replace such rejected Products as promptly as reasonably
practicable, but in no event later than ninety (90) days following receipt of
written notice of such rejection, at no additional cost to Celgene. Celgene
shall either deliver such non-conforming Products to GSK or destroy the same and
provide to GSK written documentation reasonably satisfactory to GSK to the
effect that such non-conforming Products have been destroyed in accordance with
Applicable Laws. Celgene's exclusive remedy for any non-conforming Products
shall be as provided in this Section 6.03(b).
6.04 Safety Data Exchange. Each of GSK and Celgene agree to notify each
other concerning possible Serious Adverse Events, possible Adverse Events that
are not Serious Adverse Events and possible pregnancy exposures related to the
Products within the respective time periods, and in accordance with the
procedures set forth on EXHIBIT 6.04.
6.05 Medical Information Services. On or before the Effective Date, GSK
shall provide to Celgene, GSK's current database of Medical Information Letters
regarding the Products; provided, however, that Celgene shall be solely
responsible and liable for any use or modification of such Medical Information
Letters by Celgene. GSK shall refer all requests and inquiries from healthcare
professionals and consumers of the Products to Celgene, and Celgene will provide
to GSK the telephone number to which such call will be referred. Celgene and GSK
have jointly developed written procedures for the administration of and response
to medical inquiries concerning the Products by consumers, physicians,
pharmacists and other health care professionals, as set forth in EXHIBIT 6.05.
Celgene and GSK shall each comply with the provisions thereof.
6.06 Returns and Chargebacks. Prior to the commencement of the third
Calendar Quarter after the Effective Date, GSK shall be solely and exclusively
responsible for processing any and all (i) returned Products and for the
issuance (at its expense) of any and all credits or other reimbursement
therefor, and (ii) chargebacks. From and after the commencement of the third
Calendar Quarter after the Effective Date, Celgene shall be solely and
exclusively responsible for processing any and all returned Products (including
all returned Products bearing GSK's NDCs), and for the issuance of any and all
credits or other reimbursement therefor, and for all chargebacks. Any and all
returned Products bearing GSK's NDCs received by GSK after
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the Effective Date will be destroyed by GSK, and if such return occurred after
commencement of the third Calendar Quarter after the Effective Date, GSK will,
after such destruction, forward to Celgene any accompanying documentation to
determine an appropriate customer credit. Except as otherwise provided herein,
Celgene and GSK will not bill one another for costs incurred in processing
returned Products. GSK and Celgene will use Commercially Reasonable Efforts in
requesting that customers direct all returns of any of the Products to the
appropriate Party after the Effective Date.
6.07 Product Recall. If either Celgene or GSK obtains information that
any of the Products or any portion thereof is alleged or proven not to conform
with the labeling or the Product Registration for such Products in the
Territory, it shall notify the other Party immediately and both Parties shall
cooperate fully regarding the investigation and disposition of any such matter.
GSK and Celgene shall each maintain such traceability records as are sufficient
and as may be necessary to permit a recall or field correction of any Products.
In the event (a) any applicable federal or state regulatory authority in the
Territory should issue a request, directive or order that any of the Products be
recalled, or (b) a court of competent jurisdiction orders such a recall, or (c)
GSK or Celgene determines that any of the Products already in interstate
commerce in the Territory present a risk of injury or gross deception or is
otherwise defective, misbranded and/or adulterated and that recall of such
Products is appropriate (any such event described in (a), (b) or (c), a
"Recall"), each Party shall give telephonic notice (to be confirmed in writing)
to the other within twenty-four (24) hours after becoming aware of an event
described in (a) or (b), or after making the determination described in (c). GSK
shall have sole responsibility for determining all corrective action to be taken
and to implement the Recall, but shall confer with Celgene and keep Celgene
informed on a regular basis of GSK's progress in planning and implementing the
Recall. Celgene will use Commercially Reasonable Efforts to cooperate with and
assist GSK in connection therewith as may be requested by GSK. GSK shall be
responsible for all expenses of effecting any such Recall (including any
out-of-pocket expenses incurred by Celgene in connection with such cooperation),
except to the extent such Recall is attributable to any negligence on the part
of Celgene or any material breach by Celgene of its obligations under this
Agreement, in which event Celgene will reimburse GSK for its reasonable costs
and expenses incurred that are so attributable to such negligence or material
breach by Celgene. GSK shall provide to Celgene replacement Products for any
recalled Products at GSK's sole expense, except to the extent that such Recall
is attributable to any negligence on the part of Celgene or any material breach
by Celgene of its obligations under this Agreement or any other agreement then
in force and effect between Celgene and GSK. Celgene's Annual Minimum Purchase
Requirement pursuant to Section 5.01 or 7.01 shall be reduced by the value
(based on the Net Wholesale Price) of the lots affected by such Recall.
6.08 Product Complaints.
(a) Celgene and GSK each shall maintain complaint files for Products in
accordance with Good Manufacturing Practices. Celgene and GSK each shall record
any complaints received with respect to the Products substantially in the format
attached hereto as EXHIBIT 6.08.
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(b) GSK shall promptly provide to Celgene written notice (using the
form specified in Section 6.08(a) above) of any complaints (and will provide
copies of any written complaints) received by GSK with respect to any Product.
Celgene shall promptly provide to GSK written notice (substantially in the
format specified in Section 6.08(a) above) of any complaints (and will provide
copies of any written complaints) received by Celgene with respect to any
Product. Celgene shall have responsibility for responding to all complaints, and
for promptly providing GSK with a copy of any responses to complaints, relating
to the Products, including but not limited to complaints from competitors
regarding promotional activities by Celgene. GSK shall cooperate with Celgene to
provide any information GSK, in good faith, deems necessary to respond to such
complaints. GSK shall have sole responsibility at its expense for reporting any
complaints relating to the Products to the FDA (and any other Governmental
Authority where required), including, but not limited to, complaints relating to
the manufacture of the Products as well as adverse drug experience reports.
6.09 Additional Covenants of Celgene. Celgene shall (a) not give any
Third Party purchaser of the Products any guarantee or warranty on behalf of
GSK, (b) enter into all sale contracts for the Products as a principal (as
opposed to an agent of GSK), (c) follow up and investigate customer and
tampering complaints related to the Products, and keep GSK informed, as
appropriate, as to the nature, status and resolution of such complaints on a
timely basis with sufficient information to GSK to investigate such complaints,
and (d) upon receipt by Celgene of any Product, handle, use and store the
Products in compliance with Good Manufacturing Practices and Applicable Laws.
6.10 Compliance with Applicable Law. Each Party shall use Commercially
Reasonable Efforts to maintain in full force and effect all necessary licenses,
permits and other authorizations required by Applicable Law to carry out its
duties and obligations under this Agreement. Each Party shall comply with all
Applicable Laws, provided, that Celgene shall be solely responsible for
compliance with those Applicable Laws pertaining to the marketing, promotion,
advertisement, sale and distribution of the Products. (including, without
limitation, those Applicable Laws that apply to documentation and records
retention pertaining to the distribution and use of Products within the
Territory) and GSK shall be solely responsible for compliance with those
Applicable Laws pertaining to the manufacturing and supply of the Products
(including, without limitation, those Applicable Laws that apply to
documentation and records retention pertaining to the manufacture of Products
within the Territory). Without limiting the generality of the foregoing, Celgene
shall not promote the Products for any indications not contained in the approved
NDA or in any manner in conflict with the approved labeling and all Applicable
Laws. Celgene shall store and distribute the Products and trade forms in
compliance with all Applicable Laws. Each Party will cooperate with the other to
provide such letters, documentation and other information on a timely basis as
the other Party may reasonably require to fulfill its reporting and other
obligations under Applicable Laws to applicable regulatory authorities. Except
for such amounts as are expressly required to be paid by a Party to the other
under this Agreement, each Party shall be solely responsible for any costs
incurred by it to comply with its obligations under Applicable Laws.
6.11 Reasonable Cooperation. GSK and Celgene each hereby agrees to use
Commercially Reasonable Efforts to take, or cause to be taken, all actions and
to do, or cause to
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be done, all things necessary or proper to make effective the transactions
contemplated by this Agreement, including such actions as may be reasonably
necessary to obtain approvals and consents of governmental Persons (including,
without limitation, all NDA notifications to the FDA identifying Celgene as a
distributor of the Products).
6.12 Compliance Audits.
(a) From time to time as GSK may elect during the Term (but no more
than once each Annual Period), during normal business hours and upon reasonable
notice from GSK (but not less than ten (10) Business Days' prior notice),
Celgene shall permit duly authorized representatives of GSK to review and
inspect, to the extent relevant to Celgene's marketing and distribution of the
Products, the premises, facilities, inventories of the Products, records and
documentation maintained by Celgene for the purpose of determining compliance by
Celgene with its obligations under this Agreement.
(b) From time to time as Celgene may elect during the Term (but no more
than once each Annual Period), during normal business hours and upon reasonable
advance notice from Celgene (but not less than ten (10) Business Days' notice),
GSK shall permit and, to the extent possible, cause such of its subcontractors
as shall provide services with respect to the Products to permit, duly
authorized representatives of Celgene to review and inspect, on the premises of
GSK or its relevant subcontractors each manufacturing facility for the Products
and on the premises of GSK where such records and inventory are kept, inventory
of the Products, Manufacturing Documentation and GSK's quality control records
relating to the storage of the Products to ensure compliance with Good
Manufacturing Practices, quality control standards and the packaging and
labeling for the Products; and with applicable terms of this Agreement
pertaining to the use of the Trademarks; provided, however, that except as
otherwise provided herein, nothing in the foregoing shall allow or be construed
to allow Celgene to have access to any confidential manufacturing know-how or
trade secrets of GSK or any records containing or pertaining to the same. If GSK
cannot require a subcontractor to submit to such inspection by Celgene, GSK
shall conduct any such inspection on Celgene's behalf, and will report any
results of such inspection to Celgene within sixty (60) days of completing the
inspection.
ARTICLE 7
FEES AND PAYMENTS
-----------------
7.01 Manner of Payment. All payments to be made by a Party to the other
Party pursuant to this Agreement shall be made in US dollars and by wire
transfer to the designated account below in accordance with the following wire
instructions, or such other account and instructions as may from time to time be
designated in writing by an officer of the receiving Party:
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If to GSK:
----------
Bank: Citibank - NY
SWIFT: CITIUS33
ABA Number: 021-000-089
Account Name: SmithKline Beecham Corporation
Account Number: 4073-4922
If to Celgene:
--------------
Bank: PNC Bank, N.A.
ABA Number: 031 207 607
Account Name: Celgene Corp.
Account Number: 8100 901 961
(a) Invoice Payments. Celgene shall pay all amounts invoiced by
GSK for Products shipped during any Calendar Quarter as
contemplated by, and in the manner specified in, Section 5.07.
(b) Guaranteed Minimums.
(i) Celgene acknowledges and agrees that the Annual Minimum
Purchase Requirements specified in this Agreement are, and
shall be deemed, guaranteed minimum revenue payments to GSK,
and such amounts shall be paid to GSK, in accordance with
Section 7.01(b)(ii) below, regardless of Celgene's actions,
attempted actions or omissions in marketing, promoting,
advertising, selling or distributing the Products.
(ii) With respect to any Annual Period during the Term, in the
event that the total amount invoiced by GSK under this
Agreement is less than the Annual Minimum Purchase Requirement
with respect to such Annual Period, Celgene shall pay to GSK a
sum equal to the difference. Payment of such amount will be
made on or prior to the thirtieth (30th) day of the first
(1st) month in the Annual Period immediately following the
Annual Period in which such deficit accrued.
(c) If, as a result of an assignment pursuant to Section 13.01, a
withholding tax is required by the revenue authorities in any
country by either Party, the withholding Party shall withhold
taxes on amounts paid hereunder to the other Party. The
withholding Party will deduct such taxes from such payment and
will remit the withholding tax to the proper taxing authority
on behalf of the other Party. In the event such taxing
authority routinely provides a tax receipt upon payment, the
withholding Party will procure tax receipts for any such
withholding evidencing payment of such taxes, which will be
forwarded to the other Party. The withholding Party agrees to
assist the other Party, at the other party's expense, in
claiming exemption from such deductions or withholdings under
any applicable double taxation or similar agreement or treaty.
In the event that withholding is due by a U.S. Party on
payments to a foreign Affiliate of the other Party and a
reduced rate of withholding is available under the U.S. Tax
Treaty, the foreign Affiliate of the other Party shall provide
the U.S. withholding Party a signed and completed U.S. Form
W-8BEN, Certificate of Foreign Status of Beneficial Owner for
United States Tax Withholding, to secure the reduced treaty
rate of withholding.
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7.02 No Additional Amounts. Except as set forth in Section 7.01, GSK
acknowledges and agrees that no additional amounts are due from Celgene as
consideration for any of the rights, including the exclusive distribution and
marketing rights, granted to Celgene pursuant to this Agreement.
7.03 Late Payments. In the event that any payment due under this
Agreement is not made when due, the payment shall accrue interest from the date
due at an interest rate per annum equal to the sum of the rate of interest per
annum publicly announced by Citibank, N.A. as its prime rate plus two percent
(2%); provided, however, that in no event shall such rate exceed the maximum
legal annual interest rate. The payment of such interest shall not limit a Party
from exercising any other rights it may have as a consequence of the lateness of
any payment.
7.04 Right of Offset. The Parties agree that in the event that any
payment obligation on the part of Celgene to GSK under the terms of this
Agreement is not made by Celgene when such payment is due, then in such event
and as long as such amount remains unpaid GSK shall be entitled to offset such
unpaid amount against any amounts which may otherwise be due to Celgene from
GSK.
ARTICLE 8
REPRESENTATIONS AND WARRANTIES
------------------------------
8.01 Representations and Warranties of Both Parties. Each Party hereby
represents and warrants to the other Party that, as of the Effective Date:
(a) Good Standing. Such Party is duly organized, validly existing and
in good standing under the Applicable Laws of the state of its incorporation, is
duly qualified to transact the business in which it is engaged in each
jurisdiction where failure to be so qualified would have a material adverse
effect upon its business as currently conducted, and has full corporate power
and authority to enter into this Agreement and to carry out the provisions of
this Agreement.
(b) Power and Authority. Such Party has the requisite power and
authority and the legal right to enter into this Agreement, and to perform its
obligations hereunder, and has taken all necessary corporate action on its part
to authorize the execution and delivery of the Agreement and the performance of
its obligations hereunder. All persons who have executed this Agreement on
behalf of such Party, or who will execute on behalf of such Party any agreement
or instrument contemplated hereby, have been duly authorized to do so by all
necessary corporate action.
(c) Binding Obligation. This Agreement has been duly executed and
delivered on its behalf and (assuming the due execution and delivery hereof by
the other Party) each such agreement is a legal and valid obligation binding
upon it and is enforceable in accordance with its terms, except that:
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(i) such enforcement may be subject to bankruptcy, insolvency,
reorganization, moratorium or other similar Applicable Laws
now or hereafter in effect relating to creditors rights
generally, and
(ii) such enforcement may be limited by equitable principles and
Applicable Law.
8.02 Representations and Warranties of GSK. GSK hereby represents and
warrants to Celgene that, as of the Effective Date:
(a) No Violation of Instruments or Contracts. The execution and the
delivery of this Agreement and the consummation of the transactions contemplated
hereby will not:
(i) violate the Certificate of Incorporation or By-Laws of any of
the GSK Entities;
(ii) to the best of GSK's knowledge, materially conflict with or
result in a material breach of any of the material terms,
conditions or provisions of, or constitute an express event of
default under, any material instrument, agreement, mortgage,
judgment, order, award, or decree specifically relating to the
manufacturing, distribution or sale of the Products to which any
GSK Entity is a party or by which it is bound and which would
have a material adverse effect upon the distribution or sale of
the Products as currently conducted by such GSK Entity (it being
understood that certain contracts pertaining to the sale of
Products to Third Parties may require the consent of such Third
Party for assignment of same to Celgene);
(iii) to the best of GSK's knowledge, require the affirmative
approval, consent, authorization or other order or action of any
court, governmental authority or regulatory body or of any
creditor of any of the GSK Entities, except for the
Hart-Scott-Rodino filing required in connection with the
Transfer as contemplated by Section 2.06.
(b) Compliance with Applicable Law. Each GSK Entity is, in compliance
with all requirements of Applicable Law within the Territory, except to the
extent that any noncompliance, individually or in the aggregate, would not have
a material adverse effect on the conduct of the distribution or sale of the
Products as currently conducted by such GSK Entity or the transactions
contemplated by this Agreement, including the marketing, promotion, advertising,
sale and distribution of the Products in the Territory by Celgene pursuant to
this Agreement, and would not materially and adversely affect GSK's ability to
perform its obligations under this Agreement (any such effect, a "Material
Adverse Effect").
(c) Litigation and Claims. There is no litigation, arbitration, claim,
governmental or other proceeding, or, to the knowledge of GSK, governmental
investigation pending or threatened in writing within the Territory relating to
the Products (it being understood that this sentence shall not constitute, and
shall not be deemed to constitute, a representation or warranty with respect to
the Trademarks), which, if adversely determined, would have a Material Adverse
Effect.
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(d) Contract Holder List. EXHIBIT 2.01 is a complete and accurate list
of GSK's contract holders for the Products in the Territory as of the Effective
Date.
(e) Regulatory Filings. GSK has provided Celgene with access to a
complete copy of each of the Product Registrations, including all material
amendments and supplements thereto, relating to the Products in the Territory.
GSK is the lawful holder of all rights under each of the Product Registrations.
GSK has complied in all material respects with all Applicable Laws and
regulations in connection with the preparation and submission to the FDA of each
of the Product Registrations, and each of the Product Registrations has been
approved by the FDA.
(f) Intellectual Property.
(i) GSK owns all Intellectual Property relating to the
Products;.
(ii) the Intellectual Property has been duly maintained
and has not been cancelled, expired or abandoned;
(iii) GSK has not and will not pursue any actions in
derogation of such rights or inconsistent with the
rights conferred by this Agreement;
(iv) GSK is unaware, as of the Effective Date, of any
challenges to or violation of such rights by a Third
Party.
(g) Returns and Chargebacks. EXHIBIT 8.02(g)(i) is a true and complete
report with respect to returns of the Products for the twelve (12) month period
ended December 31, 2002 and the two (2) month period ended February 28, 2003,
and EXHIBIT 8.02(g)(ii) is a true and complete report with respect to
chargebacks for the Products for the twelve (12) month period ended December 31,
2002 and the two (2) month period ended February 28, 2003.
(h) Trademarks.
(i) GSK, or an Affiliate of GSK, as the case may be, is
the owner of all of the issued Trademark
registrations listed in EXHIBIT 1.01.
(ii) The registrations for the Trademarks are in full
force and effect and have been maintained to date in
the Territory.
(iii) To the knowledge of GSK, none of the Trademarks
infringes upon any trademark or other proprietary
rights of any other Third Party in the Territory.
There is no action, suit or proceeding pending or, to
the knowledge of GSK, that has been threatened in
writing by any Third Party in the Territory against
GSK, or an Affiliate of GSK, as the case may be,
which, if adversely determined, would have a material
adverse effect upon the ability of GSK, or an
Affiliate of GSK, as the case may be, to use the
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Trademarks in connection with the marketing or sale
of the Products in the Territory as currently
conducted by GSK, or an Affiliate.
(i) Manufacturing Documentation. GSK or its Affiliates is the owner of
the Manufacturing Documentation.
8.03 Representations and Warranties of Celgene. Celgene hereby
represents and warrants to GSK that, as of the Effective Date:
(a) No Violation of Instruments or Contracts. The execution and the
delivery of this Agreement and the consummation of the transactions contemplated
hereby will not:
(i) violate the Certificate of Incorporation or By-Laws of Celgene;
(ii) to the knowledge of Celgene, materially conflict with or result
in a material breach of any of the terms, conditions or
provisions of, or constitute an express event of default under,
any material instrument, agreement, mortgage, judgment, order,
award, or decree to which Celgene is a party or by which it is
bound, or
(iii) to the knowledge of Celgene, require the affirmative approval,
consent, authorization or other order or action of any court,
governmental authority or regulatory body or of any creditor of
Celgene or any of its Affiliates, except for the
Hart-Scott-Rodino filing required in connection with the
Transfer as contemplated by Section 2.06.
(b) Compliance with Applicable Law. Celgene and its Affiliates are, and
shall use their Commercially Reasonable Efforts to ensure that they remain
throughout the Term, in compliance with all requirements of Applicable Law
within the Territory, except to the extent that any noncompliance would not have
a material adverse effect upon its ability to perform its obligations under this
Agreement.
(c) Litigation and Claims. There is no litigation, arbitration, claim,
governmental or other proceeding (formal or informal), or, to the knowledge of
Celgene, governmental investigation pending or threatened in writing within the
Territory against Celgene or any of its Affiliates which, if adversely
determined, would have a Material Adverse Effect.
8.04 No Reliance by Third Parties. The representations and warranties
of a Party set forth in this Agreement are intended for the sole and exclusive
benefit of the other Party hereto, and may not be relied upon by any Third
Party.
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ARTICLE 9
INDEMNIFICATION AND INSURANCE
-----------------------------
9.01 GSK Indemnity. GSK shall defend, indemnify and hold Celgene, its
Affiliates, and its and their respective employees, agents, officers, and
directors (each a "Celgene Party") harmless from and against any and all losses,
liabilities, damages, fees (including, until such time as GSK has notified
Celgene in writing that it will assume control of a given Celgene Claim (as
defined below), reasonable attorneys fees and costs pertaining to such Celgene
Claim), and expenses paid or payable by a Celgene Party to a Third Party and
that result from or arise in connection with a claim, suit or other proceeding
made or brought by such Third Party (the "Celgene Claim") against any Celgene
Party based on:
(a) the breach of any obligation, covenant, agreement, representation
or warranty of GSK contained in this Agreement;
(b) the distribution, marketing, advertisement, promotion or sale of
any of the Products by GSK, its Affiliates or any Third Party, and any use of
any of the Products (including without limitation Claims based on or relating to
product liability), prior to the Effective Date or following the termination or
expiration of this Agreement;
(c) any distribution, marketing, advertisement, promotion or sale of
the Products, by GSK, any of its Affiliates or any Third Party with which GSK
has entered into an agreement to manufacture, distribute, market, advertise,
promote or sell Product, outside the Territory, and any use outside the
Territory of any such Products that were sold by GSK, any of its Affiliates or
any Third Party with which GSK has entered into an agreement to manufacture,
distribute, market, advertise, promote or sell Product, outside the Territory
(including without limitation Claims based on or relating to product liability),
whether sold by GSK, its Affiliates or any Third Party with which GSK has
entered into an agreement to manufacture, distribute, market, advertise, promote
or sell Product, prior to or following the Effective Date;
(d) infringement of a Third Party's patent rights, trademarks or other
intellectual property rights by reason of Celgene's exercise of any of the
rights granted by GSK to Celgene in this Agreement, including the right to
distribute, market, advertise, promote or sell Products under this Agreement and
the sale by Celgene of Products under the Trademarks, all in accordance with the
provisions of this Agreement;
(e) the manufacture, labeling or packaging of the Products by GSK, its
Affiliates or any Third Party, and any use of the Products (including without
limitation Claims based on or relating to product liability), whether prior to,
or after, the Effective Date; or
(f) negligence or willful misconduct on the part of GSK, its Affiliates
or any Third Party in the performance of GSK's obligations under Section 3.08(a)
of this Agreement during the Transition Period;
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provided, however, that GSK shall not be obligated to indemnify a Celgene Party
for any loss, liability, damages, fees or expenses incurred by such Celgene
Party to the extent attributable solely to a breach by Celgene of any
obligation, covenant, agreement, representation or warranty of Celgene contained
in this Agreement, or to any act or omission constituting recklessness, gross
negligence or willful misconduct on the part of Celgene or a Celgene Party.
9.02 Celgene Indemnity. Celgene shall defend, indemnify and hold GSK,
its Affiliates, and its and their respective employees, agents, officers, and
directors (each a "GSK Party") harmless from and against any and all losses,
liabilities, damages, fees (including, until such time as Celgene has notified
GSK in writing that it will assume control of a given Claim, reasonable
attorneys fees and costs pertaining to such Claim), and expenses paid or payable
by a GSK Party to a Third Party (including without limitation payments that GSK
may be required to make to its licensors of any rights pertaining to any of the
Products and suppliers of any components of any Product) that result from or
arise in connection with a claim, suit or other proceeding made or brought by a
Third Party ("GSK Claim") based on:
(a) the breach by Celgene of any obligation, covenant, agreement,
representation or warranty of Celgene contained in this Agreement;
(b) the distribution, marketing, advertisement, promotion or sale of
the Products by Celgene and its Affiliates in the Territory after the Effective
Date, but not, however, any use of the Products (including without limitation
Claims based on or relating to product liability), after the Effective Date;
(c) infringement of a Third Party's trademarks, other than by reason of
the use by Celgene of the Trademarks;
(d) any failure of Celgene to comply with Applicable Laws in connection
with the distribution, marketing, advertisement, promotion or sale of the
Products, including but not limited to (i) any failure of promotional materials
developed by Celgene to comply with applicable labeling and Product
Registrations and Applicable Law, (ii) the unlawful making by Celgene of any
unsupportable or off-label claims with respect to the Products, and (iii)
unlawful communications by Celgene to its sales force (and unlawful
communications to the CSO) which otherwise result in Claims; or
(e) negligence or willful misconduct on the part of Celgene, its
Affiliates or any Third Party in the performance of Celgene's obligations under
Section 3.08(a) of this Agreement;
provided, however, that Celgene shall not be obligated to indemnify a GSK Party
for any loss, liability, damages, fees or expenses incurred by such GSK Party to
the extent attributable to a breach by GSK of any obligation, covenant,
agreement, representation or warranty of GSK contained in this Agreement, or to
any act or omission constituting negligence, recklessness, gross negligence, or
willful misconduct on the part of GSK or a GSK Party.
9.03 Control of Proceedings. Each Indemnified Party shall:
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(a) give the indemnifying Party written notice of any Claim or
potential Claim promptly after the indemnified Party receives notice of any such
Claim or Potential Claim (provided that failure to give any such notice shall
not alter or reduce the indemnification obligations of any Indemnifying Party
except to the extent that such failure caused the Indemnified Parties to incur
increased losses, liabilities, damages or fees);
(b) allow the indemnifying Party to assume exclusive control of the
defense and settlement (including all decisions relating to litigation, defense
and appeal) of any such Claim (so long as it has confirmed its indemnification
obligation responsibility to such indemnified Party under this Section 9.03 with
respect to a given Claim); provided that the controlling Party may not settle
such Claim in any manner that would require payment by the other Party, or would
materially adversely affect the rights granted to the other Party hereunder, or
would materially conflict with the terms of this Agreement, without first
obtaining the other Party's prior written consent; and
(c) reasonably cooperate with the indemnifying Party in its defense of
the Claim (including, without limitation, making documents and records available
for review and copying and making persons within its/his/her control available
for pertinent testimony) at the indemnifying Party's expense. If the
indemnifying Party defends the claim, an indemnified Party may participate in,
but not control, the defense of such Claim using attorneys of its/his/her choice
and at its/his/her sole cost and expense. An indemnifying Party shall have no
obligation or liability under this Article 9 as to any Claim for which
settlement or compromise of such claim or an offer of settlement or compromise
of such Claim is made by an indemnified Party without the prior written consent
of the indemnifying Party. If the indemnifying Party notifies the other in
writing that it will not defend the other Party against a Claim asserted against
the other Party, or if the indemnifying Party fails to defend or take other
reasonable, timely action, in response to such Claim asserted against the other
Party, the other Party shall have the right, but not the obligation, to defend
or take other reasonable action to defend its interests in such proceedings, and
shall have the right to litigate, settle or otherwise dispose of any such Claim.
9.04 Insurance. Celgene shall maintain at all times during the Term,
and thereafter for five (5) years, or as long as such insurance is reasonably
and commercially available, (i) comprehensive general liability insurance with
coverage limits of not less than Twenty Million US Dollars (USD $20,000,000),
(ii) product liability insurance with coverage limits of not less than Fifty
Million US Dollars (USD $50,000,000), (iii) workers' compensation insurance
coverage, and (iv) auto liability with coverage limits of not less than One
Million US Dollars (USD $1,000,000). Celgene will cause GSK to be named as an
additional insured on each of such insurance policies. The minimum level of
insurance set forth herein shall not be construed to create a limit on Celgene's
liability with respect to its indemnification obligations hereunder. Celgene may
elect to maintain a policy of self insurance in the foregoing amounts in
satisfaction of its obligations hereunder. Prior to the Effective Date (and each
anniversary thereof), Celgene shall furnish to GSK a certificate of insurance
evidencing such coverage as of the Effective Date (and each anniversary thereof)
and upon reasonable request by GSK at any time hereafter. Each such certificate
of insurance shall include a provision whereby thirty (30) days' written notice
must be received by GSK prior to coverage modification or cancellation by either
Celgene or the insurer. GSK shall maintain a policy of self-insurance in amounts
sufficient to cover its obligations under the Agreement.
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9.05 LIMITATION OF LIABILITY.
(a) EXCEPT AS OTHERWISE EXPRESSLY PROVIDED IN THIS AGREEMENT, IN NO
EVENT SHALL EITHER GSK OR CELGENE BE LIABLE TO THE OTHER PARTY FOR ANY
CONSEQUENTIAL, SPECIAL, INCIDENTAL OR INDIRECT DAMAGES (INCLUDING, WITHOUT
LIMITATION, ANY DAMAGES ARISING FROM THE LOSS OF BUSINESS, DATA, PROFITS OR
GOODWILL OR THE COST OF PROCUREMENT OF SUBSTITUTE GOODS, SERVICES OR TECHNOLOGY)
INCURRED OR SUFFERED BY THE OTHER PARTY WITH RESPECT TO EITHER PARTY'S
PERFORMANCE OR FAILURE TO PERFORM UNDER THIS AGREEMENT, OR FOR ANY OTHER REASON,
EVEN IF APPRISED OF THE LIKELIHOOD OF SUCH DAMAGES.
(b) The limitation of liability expressed in Section 9.05(a) above
shall not affect or otherwise limit the obligation of each Party hereunder to
indemnify each other (in accordance with the provisions of Section 9.01, 9.02
and 9.03 as applicable) for claims which are brought by Third Parties.
9.06 Survival. The rights and obligations of the Parties under this
Article 9 shall survive the termination or expiration of this Agreement.
ARTICLE 10
FORCE MAJEURE
-------------
10.01 Force Majeure. Any delays in performance by any Party under this
Agreement, other than with respect to the payment of obligations, shall not be
considered a breach of this Agreement if and to the extent caused by occurrences
beyond the reasonable control of the Party affected, including but not limited
to acts of God, embargoes, governmental restrictions, materials shortages or
failure of any supplier (where such shortage or failure is attributable to an
event of force majeure suffered by such supplier), fire, flood, explosion,
earthquake, hurricanes, storms, tornadoes, riots, wars, civil disorder, failure
of public utilities or common carriers, labor disturbances, rebellion or
sabotage. The Party suffering such occurrence shall notify the other Party as
soon as practicable of such inability and of the period for which such inability
is expected to continue, and any time for performance hereunder shall be
extended by the actual time of delay caused by the occurrence; provided, that
the Party suffering such occurrence uses Commercially Reasonable Efforts to
mitigate any damages incurred by the other Party.
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ARTICLE 11
CONFIDENTIALITY
---------------
11.01 Confidentiality.
(a) No Party shall disclose, or permit any of its Affiliates to
disclose, any Confidential Information (as defined below) to any Third Party,
except, in the case of a disclosure by GSK or any of its Affiliates, with the
prior written consent of Celgene, or, in the case of a disclosure by Celgene or
any of its Affiliates, with the prior written consent of GSK. No Party shall use
any Confidential Information for any purposes other than the exercise of its
rights and the performance of its obligations under this Agreement and/or any
other express purposes for which such information was disclosed or obtained.
Each Party may disclose Confidential Information to its employees,
representatives, consultants, professional advisors and agents who require
access to such information in performing activities consistent with the exercise
of its rights and the performance of its obligations under this Agreement and/or
any other express purposes for which such information was disclosed or obtained,
provided that each Party shall be fully responsible for any breach of this
Article 11 by its employees, representatives, consultants, professional
advisors, or agents. All Confidential Information shall be held in strict
confidence by each Party and shall be protected with the same standard of care
that such Party uses in protecting its own confidential information of a similar
nature, but in no event shall such Party use less than a reasonable standard of
care. For purposes of this Agreement, "Confidential Information" shall mean any
and all information (i) regarding the terms of this Agreement or (ii) disclosed
to or obtained by a Party pursuant to or in connection with the negotiation,
execution, delivery and performance of this Agreement or the consummation of the
transactions contemplated hereby. This Article 11 shall not apply to any
Confidential Information (1) to the extent that the Confidential Information is
publicly available or generally known other than by breach of the provisions of
this Agreement or is lawfully disclosed by a Third Party which Third Party is
not in breach of an obligation of confidentiality or otherwise prohibited from
disclosing such Confidential Information; (2) to the extent disclosure is
necessary to comply with the requirements of the United States Securities and
Exchange Commission, the London Stock Exchange Limited, the Nasdaq Stock Market
or any other Governmental Authority, in which event the Party making such
disclosure shall notify the other Party as promptly as practicable (and, if
possible, prior to making such disclosure), shall consult with the other Party
so as to minimize the extent of disclosure and shall, if practicable, seek
confidential treatment of such information by the relevant Governmental
Authority, including without limitation the United States Securities and
Exchange Commission or the London Stock Exchange Limited or the Nasdaq Stock
Market; (3) disclosed by Celgene to a Third Party subcontractor to the extent
of, and pursuant to, an effective confidentiality agreement with such Third
Party subcontractor which agreement contains confidentiality provisions
substantially similar to those contained herein and provides that GSK and its
Affiliates are Third Party beneficiaries of such agreement; (4) disclosed by GSK
to a Third Party subcontractor to the extent of, and pursuant to, an effective
confidentiality agreement with such Third Party subcontractor which agreement
contains confidentiality provisions substantially similar to those contained
herein and provides that Celgene and its Affiliates are third party
beneficiaries of such agreement; or (5) disclosure of which is reasonably
necessary in connection with (and strictly limited to) enforcement of such
Party's rights hereunder. The provisions of this Article 11 shall survive the
expiration or termination of this Agreement for a period of five (5) years from
the date of such expiration or termination of this Agreement.
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(b) The confidentiality obligations set forth in this Article 11 shall
supersede the Confidential Disclosure Agreement dated as of March 20, 2002
between the Parties ("Confidentiality Agreement"), shall govern any and all
information disclosed by either Party to the other pursuant thereto, and shall
be retroactively effective to the date of such Confidentiality Agreement.
11.02 Use of Information. Each Party shall use, and cause each of its
Affiliates to use, any Confidential Information obtained by it from the other
Party or their respective Affiliates, pursuant to this Agreement or otherwise,
solely in connection with the transactions contemplated hereby.
11.03 Relief. Each Party shall be entitled, in addition to any other
right or remedy it may have, at Applicable Law or in equity, to an injunction,
without the posting of any bond or other security, enjoining or restraining any
other Party from any violation or threatened violation of this Article 11.
ARTICLE 12
TERM; TERMINATION
-----------------
12.01 Term. This Agreement shall become effective on the Effective Date
and, unless sooner terminated as provided herein, or unless extended as provided
herein, shall expire at 11:59 EST on March 31, 2006. The period that this
Agreement is effective (the "Term") shall be automatically extended by
successive one-year periods, each effective on the first (1st) day of the
calendar year following the last day of the Term then in effect (the "Renewal
Date"), unless at least twelve (12) months prior to the Renewal Date, either
Party advises the other Party that it elects not to permit the extension of the
Term.
12.02 Breach. Failure by either Party to comply with any of its
material obligations contained in this Agreement shall constitute a default
under this Agreement, and shall entitle the other Party, subject to any cure
period set forth below and if it is not in material default hereunder, to give
notice specifying in reasonable detail the nature of the default and to exercise
the rights of termination as described herein. If any such default is with
respect to (i) any payment required to be made by Celgene pursuant to Articles 5
or 7 and is not cured within ten (10) Business Days after receipt of such
notice, or (ii) is with respect to any other obligation of either Party and it
not cured within ninety (90) days after the receipt of such notice (or, if such
default cannot be cured within such ninety (90) day period, if the Party in
default does not promptly commence and diligently continue substantive actions
to cure such default and thereafter effect full cure of such default within one
hundred twenty (120) days after receipt of the foregoing notice of default), the
notifying Party shall be entitled, without prejudice to any of its other rights
conferred on it by this Agreement and in addition to any other remedies
available to it by Applicable Law or in equity, to terminate this Agreement by
giving written notice, said termination to take effect immediately upon delivery
of such notice.
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12.03 Insolvency or Bankruptcy. In the event that (i) a Party shall
commence any case, proceeding or other action (A) under any existing or future
law of any jurisdiction, domestic or foreign, relating to bankruptcy,
insolvency, reorganization or relief of debtors, seeking to have an order of
relief entered with respect to it, or seeking to adjudicate it a bankrupt or
insolvent, or seeking reorganization, arrangement, adjustment, winding-up,
liquidation, dissolution, composition or other relief with respect to it or its
debts, or (B) seeking appointment of a receiver, trustee, custodian, conservator
or other similar official for it or for all or any substantial part of its
assets, or the Party shall make a general assignment for the benefit of its
creditors; or (ii) there shall be commenced against a Party any case, proceeding
or other action of a nature referred to in clause (i) above that (A) results in
the entry of an order for relief or any such adjudication or appointment or (B)
remains undismissed, undischarged or unbonded for a period of sixty (60) days;
or (iii) there shall be commenced against the Party any case, proceeding or
other action seeking issuance of a warrant of attachment, execution, restraint
or similar process against all or any substantial part of its assets that
results in the entry of an order for any such relief that shall not have been
vacated, discharged, or stayed or bonded pending appeal within sixty (60) days
from the entry thereof; or (iv) the Party shall take any action in furtherance
of, or indicating its consent to, approval of, or acquiescence in, any of the
acts set forth in clauses (i), (ii), or (iii) above; or (v) the Party shall
generally not, or shall be unable to, or shall admit in writing its inability
to, pay its debts as they become due; then, in addition to any other remedies
available to the other Party by Applicable Law or in equity, the other Party may
terminate this Agreement by giving written notice to the other Party, which
shall be effective immediately upon delivery of such notice, whereupon, all
amounts owing under this Agreement shall immediately become due and payable.
12.04 Other Termination. At any time after there shall have occurred a
Recall of any of the Products or a withdrawal of any of the Products by GSK,
then, in addition to any other remedies available to Celgene under Applicable
Law, in equity or under this Agreement, Celgene may terminate this Agreement by
giving written notice to GSK, which shall be effective on such date as shall be
designated in such notice.
12.05 Effect of Termination or Expiration.
(a) Upon any early termination of this Agreement or upon expiration of
this Agreement pursuant to Section 12.01 Celgene shall promptly:
(i) return to GSK all relevant records, materials or Confidential
Information relating to the Products in its (or any of its any
Affiliate's or contractors') possession or control;
(ii) cease all marketing, sale, promotion, advertising, and
distribution of the Products, and
(iii) discontinue use of the Trademarks, destroy all advertising or
other printed materials bearing the Trademarks, and Celgene's
right to use the Trademarks for the Products in the Territory
shall terminate.
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(b) Upon any early termination of this Agreement or upon expiration of
this Agreement pursuant to Section 12.01, any acceptance by GSK of any order
from Celgene on the sale of any Products by GSK to Celgene after any such
termination or expiration of this Agreement shall not be construed as a renewal
or extension of this Agreement or as a waiver of termination or expiration
thereof.
(c) Upon any early termination of this Agreement by either Party for
any reason or upon expiration of this Agreement pursuant to Section 12.01,
Celgene shall, at its option, (i) sell to GSK and GSK shall purchase all of
Celgene's remaining inventory of Products (except Products with an expiration
date of less than twelve (12) months, that Celgene shall destroy) at the
per-unit price paid by Celgene to GSK hereunder for such Products or (ii) have
the right to continue to market, sell and distribute all of its remaining
inventory of Products.
12.06 Accrued Rights, Surviving Obligations.
(a) Termination or expiration of this Agreement for any reason shall be
without prejudice to any rights that shall have accrued to the benefit of either
Party prior to such termination or expiration. Such termination or expiration
shall not relieve either Party from obligations that are expressly indicated to
survive termination or expiration of this Agreement.
(b) Without limiting the generality of the last sentence of Section
12.06(a), all of the Parties' rights and obligations under Articles 9 and 11
shall survive any termination or expiration of this Agreement in accordance with
their terms.
12.07 Residual Payments. GSK shall pay to Celgene residual payments
following the expiration or termination of this Agreement, as follows:
(a) for the first twelve (12) month period following the
expiration or termination of this Agreement, and payable
within forty five (45) days after such expiration or
termination, an amount equal to thirty percent (30%) of
Average Annual Net Sales; and
(ii) for the second twelve (12) month period following the
expiration or termination of this Agreement, and payable
within forty-five (45) days after the first anniversary of
such expiration of termination, an amount equal to fifteen
percent (15%) Average Annual Net Sales.
For purposes of this Agreement, "Average Annual Net Sales" shall be calculated
as follows:
(A/B) x 12
where,
A = total Net Sales from the Effective Date through the date of
expiration or termination; and
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B = the total number of months that have elapsed from the Effective
Date through the date of expiration or termination.
In no event are the payments set forth above to be considered
cumulative payments (i.e., more than forty-five percent (45%) of Average Annual
Net Sales). In the event that it is determined that Celgene is in breach of the
payment obligations under Section 5.07 of this Agreement, GSK shall be entitled
to offset any amounts due and owing GSK against the residual payments due and
owing Celgene under this Section 12.07.
ARTICLE 13
GENERAL PROVISIONS
------------------
13.01 Assignment. Neither Party shall assign or otherwise transfer this
Agreement or any interest herein or right hereunder without the prior written
consent of the other Party, and any such purported assignment, transfer or
attempt to assign or transfer any interest herein or right hereunder shall be
void and of no effect; except that (a) each Party may assign its rights and
obligations hereunder to an Affiliate, (b) GSK may subcontract its rights to
manufacture Products to a Third Party, (c) Celgene may subcontract to Third
Parties without GSK's consent unless such subcontract relates to the performance
of Celgene's sales and marketing obligations under this Agreement, in which
event, GSK's consent shall not be unreasonably withheld (although, with respect
to any subcontract, Celgene shall remain primarily responsible for all of its
obligations and agreements set forth herein, notwithstanding such assignment or
subcontract). Notwithstanding the foregoing, either Party may assign this
Agreement and its rights and obligations hereunder in connection with a sale or
transfer of all or substantially all of its business, and no assignment shall be
deemed to have occurred in the event of its merger or consolidation or change in
control or similar transaction. It is understood and agreed, however, that any
assignment of this Agreement in accordance with the terms hereof, shall be fully
binding upon, and enforceable against, the permitted successors and assigns of
the Parties without further action on the part of the Parties hereto or the
permitted successors or assigns thereof.
13.02 Non-Waiver. Any failure on the part of a Party to enforce at any
time or for any period of time any of the provisions of this Agreement shall not
be deemed or construed to be a waiver of such provisions or of any right of such
Party thereafter to enforce each and every such provision on any succeeding
occasion or breach thereof.
13.03 Notices. Unless otherwise explicitly set forth herein, any notice
required or permitted to be given hereunder shall be in writing and shall be
delivered personally by hand, or sent by reputable overnight courier, signature
required, to the addresses of each Party set forth below or to such other
address or addresses as shall be designated in writing in the same matter:
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If to GSK: SmithKline Beecham Corporation
d/b/a GlaxoSmithKline
5 Moore Drive
Research Triangle Park, NC 27709
Attention: Director
US Business Development
Telephone: 919-483-7801
Facsimile: 919-483-0269
With a copy to: SmithKline Beecham Corporation
d/b/a GlaxoSmithKline
R & D Legal Operations
2301 Renaissance Blvd. (Bldg. 510)
King of Prussia, PA 19406
Attention: Vice President & Associate General Counsel
Telephone: 610-787-3626
Facsimile: 610-787-7084
If to Celgene: Celgene Corporation
7 Powder Horn Drive
Warren, New Jersey 07059
Attention: President
Telephone: 732-271-1001
Facsimile: 732-805-3931
With a copy to: Proskauer Rose LLP
1585 Broadway
New York, New York 10036
Attention: Robert A. Cantone, Esq.
Telephone: 212-969-3235
Facsimile: 212-969-2900
13.04 Amendments. This Agreement may be waived, amended, supplemented
or modified only by a written agreement executed by each of the Parties hereto.
13.05 Entirety of Agreement. This Agreement, with the Exhibits and
Schedules attached hereto, and the Services Agreement contain the entire
understanding of the Parties with respect to the subject matter hereof and
thereof and supersede all previous and contemporaneous verbal and written
agreements, representations and warranties with respect to such subject matter.
This Agreement shall not be strictly construed against either Party hereto.
13.06 Public Announcements. The form and content of any public
announcement to be made by one Party regarding the subject matter of this
Agreement, shall be subject to the prior written consent of the other Party
(which consent may not be unreasonably withheld or delayed), except as may be
required by Applicable Law (including, without limitation, disclosure
requirements of the SEC, NASDAQ, or any other stock exchange) in which event the
other Party shall use Commercially Reasonable Efforts to give the other Party
reasonable advance notice and reasonable opportunity to review any such
disclosure.
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13.07 Governing Law. This Agreement shall be governed by and construed
in accordance with the Applicable Laws of the State of New York, without regard
to its conflicts of law principles.
13.08 Relationship of the Parties. In making and performing this
Agreement, the Parties are acting, and intend to be treated, as independent
entities and nothing contained in this Agreement shall be construed or implied
to create an agency, partnership, joint venture, or employer and employee
relationship between GSK and Celgene. Except as otherwise expressly provided
herein, neither Party may make any representation, warranty or commitment,
whether express or implied, on behalf of or incur any charges or expenses for or
in the name of the other Party. No Party shall be liable for the act of any
other Party unless such act is expressly authorized in writing by both Parties
hereto.
13.9 Counterparts. This Agreement shall become binding when any one or
more counterparts hereof, individually or taken together, shall bear the
signatures of each of the Parties hereto. This Agreement may be executed in any
number of counterparts, each of which shall be deemed an original as against the
Party whose signature appears thereon, but all of which taken together shall
constitute but one and the same instrument.
13.10 Severability. If any part of this Agreement is declared invalid
by any legally governing authority having jurisdiction over either Party, then
such declaration shall not affect the remainder of the Agreement and the Parties
shall revise the invalidated part in a manner that will render such provision
valid without impairing the Parties' original intent.
13.11 Cumulative Rights. Except as herein expressly provided, the
rights, powers and remedies hereunder shall be in addition to, and not in
limitation of, all rights, powers and remedies provided at Applicable Law or in
equity, or under any other agreement between the Parties, and all of such
rights, powers and remedies shall be cumulative, and may be exercised
successively or cumulatively.
13.12 No Other Rights. No rights or licenses in or to either Party's
patent rights, know-how, copyrights or trademarks are granted by a Party to the
other, or shall be created or implied hereunder, except those licenses and
rights that are expressly granted in this Agreement.
13.13 Expenses. GSK and Celgene shall each bear their own direct and
indirect expenses incurred in connection with the negotiation and preparation of
this Agreement and, except as otherwise expressly set forth in this Agreement,
the performance of the obligations contemplated hereby.
13.14 Disputes. In the event there shall occur any dispute between the
Parties with respect to any matter under this Agreement, the Parties shall
endeavor to resolve such dispute by good faith negotiations which shall include,
unless earlier resolved, good faith discussion between the chief operating
officer of Celgene and the President of US Pharmaceuticals of GSK.
46
<PAGE>
[End of text; signature page follows]
47
<PAGE>
IN WITNESS WHEREOF, the Parties hereto have duly executed this
Agreement as of the Effective Date.
SmithKline Beecham Corporation, d/b/a
GlaxoSmithKline
By:
-----------------------------------------
Name: Don Parman
Title: Vice President and Secretary
Celgene Corporation
By:
-----------------------------------------
Name: Sol Barer
Title: President and Chief Operating Officer
48
<PAGE>
Exhibits
--------
1.01A Intellectual Property
1.01B Trademarks
2.01 Contract Holder List
2.01(d) Letter to Customers
5.01 Current Package Inserts (PI)
5.02(c) Semi-Annual Supply Schedule Procedures
5.04 Minimum Order Amounts
5.08 Alkeran Manufacturing Matrix
6.04 Safety Monitoring of Alkeran
6.05 Procedures for Submitting Medical Inquiries
6.08 Procedures for Reporting Product Complaints
8.02(g)(i) Product Returns for 2002 and January and February 2003
8.02(g)(ii) Indirect Chargeback History for 2002 and January and February
2003
<page>
EXHIBIT 1.01A
INTELLECTUAL PROPERTY
---------------------
Patent Number Expiration Date
------------- ---------------
1. US Patent No. 4,997,651 2008
2. Patent Application U.S. Ser. No. 60/392,186
2
<page>
EXHIBIT 1.01B
TRADEMARKS
TRADEMARK Reg. No.
--------- -------
ALKERAN 0681707
3
<page>
EXHIBIT 2.01
CONTRACT HOLDER LIST
--------------------
Alkeran
Contracts
Contract Exp
Date >=10/22/2002
Sls period: 10/2001 - 09/2002
CONTRACT TITLE MARKET TYPE
================================================================================
AMERINET ACUTE GROUP PURCHASING ORGANIZATION
AMERINET ALTERNATE ALTERNATE HEALTH CARE
AMERINET HHC/SC Alternate & Home Health
AMERINET LINE-ITEM 304522 GROUP PURCHASING ORGANIZATION
AMERINET SURGICTR/HOME HLTH HOME HEALTH CARE
BROADLANE ACUTE GROUP PURCHASING ORGANIZATION
BROADLANE ALTERNATE ALTERNATE HEALTH CARE
BROADLANE HOME HEALTH CARE HOME HEALTH CARE
BUREAU OF PRISONS BUYING GRP FEDERAL
CHPPS GROUP PURCHASING ORGANIZATION
Consorta Line Item GROUP PURCHASING ORGANIZATION
Consorta Line Item Alternate ALTERNATE HEALTH CARE
Consorta Line Item HHC/Physici HOME HEALTH CARE
DUKE UNIVERSITY UNIVERSITY
FEDERAL SUPPLY SCHEDULE (OGA) FEDERAL
FEDERAL SUPPLY SCHEDULE (OGA) FEDERAL
FSS/BIG 4 FEDERAL
FSS/BIG 4 FEDERAL
FSS/BIG 4 FEDERAL
FSS/BIG 4/NAT'L AWARD-ZOF TABS FEDERAL
FSS/BIG 4/NAT'L AWARD-ZOF TABS FEDERAL
FSS/DOD FEDERAL
FSS/DOD FEDERAL
FSS/DUAL/NAT'L AWARD-ZOF TABS FEDERAL
FSS/OGA FEDERAL
GSK Orange Card PATIENT ASSISTANCE
HC PHARMACY CENTRAL, INC. GROUP PURCHASING ORGANIZATION
HEALTH SVS CORP of AMER - COMM GROUP PURCHASING ORGANIZATION
HEALTH SVS CORP OF AMER NonCom GROUP PURCHASING ORGANIZATION
HEALTHCARE STRATEGIC INITIATIV ONCOLOGY CLINIC
HEALTHWORKS, INC. HOSPITAL SYSTEM
HEM ONC LEADERSHIP NET ONCOLOGY CLINIC
INDEPENDENT ONCOLOGY SERVICES ONCOLOGY CLINIC
INNOVATIVE PURCHASING CONCEPTS GROUP PURCHASING ORGANIZATION
INNOVATIX HOME HEALTH CARE
INSOURCE HEALTH SERVICES GROUP PURCHASING ORGANIZATION
INSOURCE SURGI-CENTER SURGICAL CENTER
IVMED/IHCC Inc. HOME HEALTH CARE
Joint Purchasing Corporation GROUP PURCHASING ORGANIZATION
LOUISIANA STATE UNIV HOSPITAL CITY, COUNTY, STATE
Managed Healthcare Infusion HOME HEALTH CARE
4
<PAGE>
Managed Healthcare Infusion HOME HEALTH CARE
MedAssets Alternate Care ALTERNATE HEALTH CARE
MedAssets HSCA, Inc. GROUP PURCHASING ORGANIZATION
MedAssets Surgery Center/HHC SURGICAL CENTER
Memorial Med Ctr of Tulsa HOSPITAL
MHA Long Term Care NURSING HOME PROVIDER
MHA/Medecon City County State CITY, COUNTY, STATE
MHA/MEDECON UNIV LINE ITEM GROUP PURCHASING ORGANIZATION
MIDWESTERN REGIONAL MED CTR HOSPITAL
Minnesota Multistate Governmen CITY, COUNTY, STATE
Novation Acute GROUP PURCHASING ORGANIZATION
Novation Acute GROUP PURCHASING ORGANIZATION
Novation Alternate ALTERNATE HEALTH CARE
Novation Alternate ALTERNATE HEALTH CARE
Novation HHC HOME HEALTH CARE
Novation LLC GROUP PURCHASING ORGANIZATION
NPA NCM GROUP PURCHASING ORGANIZATION
NYC HLTH & HOSP CORP CITY, COUNTY, STATE
ONCOLOGY ASSOCIATES ONCOLOGY CLINIC
ONCOLOGY EXPRESS ONCOLOGY CLINIC
ONCOLOGY NETWORK OF CT ONCOLOGY CLINIC
OWEN HEALTHCARE ALTERNATE HEALTH CARE
OWEN HEALTHCARE HOME HEALTH CARE
OWEN HEALTHCARE LTC/NHP NURSING HOME PROVIDER
OWEN INJECTION PRODUCTS GROUP PURCHASING ORGANIZATION
OWEN ORAL PRODUCTS GROUP PURCHASING ORGANIZATION
PACT Acute Care GROUP PURCHASING ORGANIZATION
PACT Alternate ALTERNATE HEALTH CARE
PACT HomeHealthCare Alternate & Home Health
PACT INJECTION GROUP PURCHASING ORGANIZATION
PACT ORAL PRODUCTS GROUP PURCHASING ORGANIZATION
Pharmaceutical Buyers Inc. HOME HEALTH CARE
PHS GRANTEES PHS
PHS GRANTEES PHS
PHS GRANTEES PHS
PHS GRANTEES PHS
PHS GRANTEES PHS
PHS GRANTEES PHS
PREMIER, INC. GROUP PURCHASING ORGANIZATION
PREMIER, INC./AHC ALTERNATE HEALTH CARE
PREMIER, INC. ACUTE CARE GROUP PURCHASING ORGANIZATION
PREMIER, INC. ALTERNATE SITE ALTERNATE HEALTH CARE
PREMIER, INC. HOME HEALTH CARE HOME HEALTH CARE
PREMIER, INC. LONG TERM CARE NURSING HOME PROVIDER
RESPONSE ONCOLOGY ONCOLOGY CLINIC
SHARED SERVICES HEALTHCARE GROUP PURCHASING ORGANIZATION
Shared Services Healthcare GROUP PURCHASING ORGANIZATION
SHELBY MEDICAL ONCOLOGY CLINIC
SOUTHERN ONC ASSOC OF PRACTICE ONCOLOGY CLINIC
State of NY - DOC CITY, COUNTY, STATE
STATE OF SOUTH CAROLINA CITY, COUNTY, STATE
STATE VETERANS HOME FEDERAL
TENET ORAL & INJ. GROUP PURCASHING ORGANIZATION
The Johns Hopkins - Alternate HOME HEALTH CARE
THE REGENTS OF THE UNIV OF MI UNIVERSITY
5
<page>
EXHIBIT 2.01(d)
LETTER TO CUSTOMERS
-------------------
GLAXOSMITHKLINE
CELGENE CORPORATION
Any Contract Holder
123 Main St.
Any-town, USA 99999
To Whom It May Concern:
Effective March 31, 2003, GSK has appointed Celgene Corporation as the exclusive
distributor in the United States for the products listed below . Accordingly and
except as clarified below, both you and GSK are hereby released from all
obligations (including, but not limited to, product requirements, administrative
service fees, rebates, and any other terms and conditions of sale) under your
agreement with GSK with respect to the products below.
GSK will provide contract administration services related to existing contracts.
GSK will also be providing order processing and shipping services on behalf of
Celgene Corporation for a limited period of time until further notice. Any
future contracting will be the responsibility of Celgene. Meanwhile, Celgene has
instructed GSK to honor all contract discounts for these products for thirty
(30) days from the date of this letter.
-------------------------------------------------------------------
Product Name Size NDC
-------------------------------------------------------------------
Alkeran Injection 50MG 00173-0130-93
-------------------------------------------------------------------
Alkeran Tablets 2MG 00173-0045-35
-------------------------------------------------------------------
6
<page>
Until futher notice, any phone inquiries should be directed to Contact Name,
Director, Contract Operations, GSK at 1-800-545-2965 or to Celgene Customer Care
at 1-888-4Celgen (1-888-423-5436).
Sincerely,
-----------------------
Vice President, Pricing Strategy & Commercial Support Services
GlaxoSmithKline
-----------------------
Dwight D'Iorio
Executive Director, Sales
Celgene Corporation
7
<page>
EXHIBIT 5.01
CURRENT PACKAGE INSERTS
-----------------------
PRODUCT INFORMATION
ALKERAN(R)
(MELPHALAN HYDROCHLORIDE)
FOR INJECTION
--------------------------------------------------------------------------------
WARNING: Melphalan should be administered under the supervision of a qualified
physician experienced in the use of cancer chemotherapeutic agents. Severe bone
marrow suppression with resulting infection or bleeding may occur. Controlled
trials comparing intravenous (IV) to oral melphalan have shown more
myelosuppression with the IV formulation. Hypersensitivity reactions, including
anaphylaxis, have occurred in approximately 2% of patients who received the IV
formulation. Melphalan is leukemogenic in humans. Melphalan produces chromosomal
aberrations in vitro and in vivo and, therefore, should be considered
potentially mutagenic in humans.
--------------------------------------------------------------------------------
DESCRIPTION: Melphalan, also known as L-phenylalanine mustard, phenylalanine
mustard, L-PAM, or L-sarcolysin, is a phenylalanine derivative of nitrogen
mustard. Melphalan is a bifunctional alkylating agent that is active against
selected human neoplastic diseases. It is known chemically as
4-[bis(2-chloroethyl)amino]-L-phenylalanine. The molecular formula is
C13H18Cl2N2O2 and the molecular weight is 305.20. The structural formula is:
[GRAPHIC OMITTED]
Melphalan is the active L-isomer of the compound and was first synthesized
in 1953 by Bergel and Stock; the D-isomer, known as medphalan, is less active
against certain animal tumors, and the dose needed to produce effects on
chromosomes is larger than that required with the L-isomer. The racemic (DL-)
form is known as merphalan or sarcolysin.
Melphalan is practically insoluble in water and has a pKa1 of ~2.5.
ALKERAN for Injection is supplied as a sterile, nonpyrogenic, freeze-dried
powder. Each single-use vial contains melphalan hydrochloride equivalent to 50
mg melphalan and 20 mg povidone. ALKERAN for Injection is reconstituted using
the sterile diluent provided. Each vial of sterile diluent contains sodium
citrate 0.2 g, propylene glycol 6.0 mL, ethanol (96%) 0.52 mL, and Water for
Injection to a total of 10 mL. ALKERAN for Injection is administered
intravenously.
CLINICAL PHARMACOLOGY: Melphalan is an alkylating agent of the
bischloroethylamine type. As a result, its cytotoxicity appears to be related to
the extent of its interstrand cross-linking with DNA, probably by binding at the
N7 position of guanine. Like other bifunctional alkylating agents, it is active
against both resting and rapidly dividing tumor cells.
8
<PAGE>
PHARMACOKINETICS: The pharmacokinetics of melphalan after IV administration has
been extensively studied in adult patients. Following injection, drug plasma
concentrations declined rapidly in a biexponential manner with distribution
phase and terminal elimination phase half-lives of approximately 10 and 75
minutes, respectively. Estimates of average total body clearance varied among
studies, but typical values of approximately 7 to 9 mL/min per kg (250 to 325
mL/min per m2) were observed. One study has reported that on repeat dosing of
0.5 mg/kg every 6 weeks, the clearance of melphalan decreased from 8.1 mL/min
per kg after the first course, to 5.5 mL/min per kg after the third course, but
did not decrease appreciably after the third course. Mean (+/-SD) peak melphalan
plasma concentrations in myeloma patients given IV melphalan at doses of 10 or
20 mg/m2 were 1.2 +/- 0.4 and 2.8 +/- 1.9 mcg/mL, respectively.
The steady-state volume of distribution of melphalan is 0.5 L/kg.
Penetration into cerebrospinal fluid (CSF) is low. The extent of melphalan
binding to plasma proteins ranges from 60% to 90%. Serum albumin is the major
binding protein, while (alpha)1-acid glycoprotein appears to account for about
20% of the plasma protein binding. Approximately 30% of the drug is (covalently)
irreversibly bound to plasma proteins. Interactions with immunoglobulins have
been found to be negligible.
Melphalan is eliminated from plasma primarily by chemical hydrolysis to
monohydroxymelphalan and dihydroxymelphalan. Aside from these hydrolysis
products, no other melphalan metabolites have been observed in humans. Although
the contribution of renal elimination to melphalan clearance appears to be low,
one study noted an increase in the occurrence of severe leukopenia in patients
with elevated BUN after 10 weeks of therapy.
CLINICAL TRIAL: A randomized trial compared prednisone plus IV melphalan to
prednisone plus oral melphalan in the treatment of myeloma. As discussed below,
overall response rates at week 22 were comparable; however, because of changes
in trial design, conclusions as to the relative activity of the 2 formulations
after week 22 are impossible to make.
Both arms received oral prednisone starting at 0.8 mg/kg per day with doses
tapered over 6 weeks. Melphalan doses in each arm were: Arm 1 Oral melphalan
0.15 mg/kg per day x 7 followed by 0.05 mg/kg per day when WBC began to rise.
Arm 2 IV melphalan 16 mg/m2 q 2 weeks x 4 (over 6 weeks) followed by the same
dose every 4 weeks.
Doses of melphalan were adjusted according to the following criteria:
TABLE 1: CRITERIA FOR DOSAGE ADJUSTMENT IN A RANDOMIZED CLINICAL TRIAL
------------------------------------------------------------------------
WBC/mm3 Platelets Percent of Full Dose
------------------------------------------------------------------------
=>4000 =>100,000 100
------------------------------------------------------------------------
=>3000 =>75,000 75
------------------------------------------------------------------------
=>2000 =>50,000 50
------------------------------------------------------------------------
<2000 <50,000 0
------------------------------------------------------------------------
One hundred seven patients were randomized to the oral melphalan arm and 203
patients to the IV melphalan arm. More patients had a poor-risk classification
(58% versus 44%) and high tumor load (51% versus 34%) on the oral compared to
the IV arm (P<0.04). Response rates at week 22 are shown in the following table:
9
<PAGE>
TABLE 2: RESPONSE RATES AT WEEK 22
-----------------------------------------------------------------------------
Evaluable Responders
Initial Arm Patients n (%) P
-----------------------------------------------------------------------------
Oral melphalan 100 44 (44%)
----------------------------------------------------------------- P>0.2
IV melphalan 195 74 (38%)
-----------------------------------------------------------------------------
Because of changes in protocol design after week 22, other efficacy
parameters such as response duration and survival cannot be compared.
Severe myelotoxicity (WBC <=1000 and/or platelets <=25,000) was more common
in the IV melphalan arm (28%) than in the oral melphalan arm (11%).
An association was noted between poor renal function and myelosuppression;
consequently, an amendment to the protocol required a 50% reduction in IV
melphalan dose if the BUN was =>30 mg/dL. The rate of severe leukopenia in the
IV arm in the patients with BUN over 30 mg/dL decreased from 50% (8/16) before
protocol amendment to 11% (3/28) (P = 0.01) after the amendment.
Before the dosing amendment, there was a 10% (8/77) incidence of
drug-related death in the IV arm. After the dosing amendment, this incidence was
3% (3/108). This compares to an overall 1% (1/100) incidence of drug-related
death in the oral arm.
INDICATIONS AND USAGE: ALKERAN for Injection is indicated for the palliative
treatment of patients with multiple myeloma for whom oral therapy is not
appropriate.
CONTRAINDICATIONS: Melphalan should not be used in patients whose disease has
demonstrated prior resistance to this agent. Patients who have demonstrated
hypersensitivity to melphalan should not be given the drug.
WARNINGS: MELPHALAN SHOULD BE ADMINISTERED IN CAREFULLY ADJUSTED DOSAGE BY OR
UNDER THE SUPERVISION OF EXPERIENCED PHYSICIANS WHO ARE FAMILIAR WITH THE DRUG'S
ACTIONS AND THE POSSIBLE COMPLICATIONS OF ITS USE.
As with other nitrogen mustard drugs, excessive dosage will produce marked
bone marrow suppression. Bone marrow suppression is the most significant
toxicity associated with ALKERAN for Injection in most patients. Therefore, the
following tests should be performed at the start of therapy and prior to each
subsequent dose of ALKERAN: platelet count, hemoglobin, white blood cell count,
and differential. Thrombocytopenia and/or leukopenia are indications to withhold
further therapy until the blood counts have sufficiently recovered. Frequent
blood counts are essential to determine optimal dosage and to avoid toxicity.
Dose adjustment on the basis of blood counts at the nadir and day of treatment
should be considered.
Hypersensitivity reactions including anaphylaxis have occurred in
approximately 2% of patients who received the IV formulation (see ADVERSE
REACTIONS). These reactions usually occur after multiple courses of treatment.
Treatment is symptomatic. The infusion should be terminated immediately,
followed by the administration of volume expanders, pressor agents,
corticosteroids, or antihistamines at the discretion of the physician. If a
hypersensitivity reaction occurs, IV or oral melphalan should not be
readministered since hypersensitivity reactions have also been reported with
oral melphalan.
10
<PAGE>
CARCINOGENESIS: Secondary malignancies, including acute nonlymphocytic leukemia,
myeloproliferative syndrome, and carcinoma, have been reported in patients with
cancer treated with alkylating agents (including melphalan). Some patients also
received other chemotherapeutic agents or radiation therapy. Precise
quantitation of the risk of acute leukemia, myeloproliferative syndrome, or
carcinoma is not possible. Published reports of leukemia in patients who have
received melphalan (and other alkylating agents) suggest that the risk of
leukemogenesis increases with chronicity of treatment and with cumulative dose.
In one study, the 10-year cumulative risk of developing acute leukemia or
myeloproliferative syndrome after oral melphalan therapy was 19.5% for
cumulative doses ranging from 730 to 9652 mg. In this same study, as well as in
an additional study, the 10-year cumulative risk of developing acute leukemia or
myeloproliferative syndrome after oral melphalan therapy was less than 2% for
cumulative doses under 600 mg. This does not mean that there is a cumulative
dose below which there is no risk of the induction of secondary malignancy. The
potential benefits from melphalan therapy must be weighed on an individual basis
against the possible risk of the induction of a second malignancy.
Adequate and well-controlled carcinogenicity studies have not been conducted
in animals. However, intraperitoneal (IP) administration of melphalan in rats
(5.4 to 10.8 mg/m2) and in mice (2.25 to 4.5 mg/m2) 3 times per week for 6
months followed by 12 months post-dose observation produced peritoneal sarcoma
and lung tumors, respectively.
MUTAGENESIS: Melphalan has been shown to cause chromatid or chromosome damage in
humans. Intramuscular administration of melphalan at 6 and 60 mg/m2 produced
structural aberrations of the chromatid and chromosomes in bone marrow cells of
Wistar rats.
IMPAIRMENT OF FERTILITY: Melphalan causes suppression of ovarian function in
premenopausal women, resulting in amenorrhea in a significant number of
patients. Reversible and irreversible testicular suppression have also been
reported.
PREGNANCY: Pregnancy Category D. Melphalan may cause fetal harm when
administered to a pregnant woman. While adequate animal studies have not been
conducted with IV melphalan, oral (6 to 18 mg/m2 per day for 10 days) and IP (18
mg/m2) administration in rats was embryolethal and teratogenic. Malformations
resulting from melphalan included alterations of the brain (underdevelopment,
deformation, meningocele, and encephalocele) and eye (anophthalmia and
microphthalmos), reduction of the mandible and tail, as well as hepatocele
(exomphaly). There are no adequate and well-controlled studies in pregnant
women. If this drug is used during pregnancy, or if the patient becomes pregnant
while taking this drug, the patient should be apprised of the potential hazard
to the fetus. Women of childbearing potential should be advised to avoid
becoming pregnant.
PRECAUTIONS:
GENERAL: In all instances where the use of ALKERAN for Injection is considered
for chemotherapy, the physician must evaluate the need and usefulness of the
drug against the risk of adverse events. Melphalan should be used with extreme
caution in patients whose bone marrow reserve may have been compromised by prior
irradiation or chemotherapy or whose marrow function is recovering from previous
cytotoxic therapy.
Dose reduction should be considered in patients with renal insufficiency
receiving IV melphalan. In one trial, increased bone marrow suppression was
observed in patients with BUN levels =>30 mg/dL. A 50% reduction in the IV
melphalan dose decreased the incidence of severe bone marrow suppression in the
latter portion of this study.
11
<PAGE>
INFORMATION FOR PATIENTS: Patients should be informed that the major acute
toxicities of melphalan are related to bone marrow suppression, hypersensitivity
reactions, gastrointestinal toxicity, and pulmonary toxicity. The major
long-term toxicities are related to infertility and secondary malignancies.
Patients should never be allowed to take the drug without close medical
supervision and should be advised to consult their physicians if they experience
skin rash, signs or symptoms of vasculitis, bleeding, fever, persistent cough,
nausea, vomiting, amenorrhea, weight loss, or unusual lumps/masses. Women of
childbearing potential should be advised to avoid becoming pregnant.
LABORATORY TESTS: Periodic complete blood counts with differentials should be
performed during the course of treatment with melphalan. At least one
determination should be obtained prior to each dose. Patients should be observed
closely for consequences of bone marrow suppression, which include severe
infections, bleeding, and symptomatic anemia (see WARNINGS).
DRUG INTERACTIONS: The development of severe renal failure has been reported in
patients treated with a single dose of IV melphalan followed by standard oral
doses of cyclosporine. Cisplatin may affect melphalan kinetics by inducing renal
dysfunction and subsequently altering melphalan clearance. IV melphalan may also
reduce the threshold for BCNU lung toxicity. When nalidixic acid and IV
melphalan are given simultaneously, the incidence of severe hemorrhagic necrotic
enterocolitis has been reported to increase in pediatric patients.
CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY: See WARNINGS section.
Pregnancy: Teratogenic Effects: Pregnancy Category D: See WARNINGS section.
Nursing Mothers: It is not known whether this drug is excreted in human milk. IV
melphalan should not be given to nursing mothers.
PEDIATRIC USE: The safety and effectiveness in pediatric patients have not been
established.
GERIATRIC USe: Clinical experience with ALKERAN has not identified
differences in responses between the elderly and younger patients. In general,
dose selection for an elderly patient should be cautious, reflecting the greater
frequency of decreased hepatic, renal, or cardiac function, and of concomitant
disease or other drug therapy.
ADVERSE REACTIONS (see OVERDOSAGE): The following information on adverse
reactions is based on data from both oral and IV administration of melphalan as
a single agent, using several different dose schedules for treatment of a wide
variety of malignancies.
HEMATOLOGIC: The most common side effect is bone marrow suppression. White blood
cell count and platelet count nadirs usually occur 2 to 3 weeks after treatment,
with recovery in 4 to 5 weeks after treatment. Irreversible bone marrow failure
has been reported.
GASTROINTESTINAL: Gastrointestinal disturbances such as nausea and vomiting,
diarrhea, and oral ulceration occur infrequently. Hepatic disorders ranging from
abnormal liver function tests to clinical manifestations such as hepatitis and
jaundice have been reported. Hepatic veno-occlusive disease has been reported.
HYPERSENSITIVITY: Acute hypersensitivity reactions including anaphylaxis were
reported in 2.4% of 425 patients receiving ALKERAN for Injection for myeloma
(see WARNINGS). These reactions were characterized by urticaria, pruritus,
edema, and in some patients, tachycardia, bronchospasm, dyspnea, and
hypotension. These patients appeared to respond to antihistamine and
corticosteroid therapy. If a hypersensitivity reaction occurs, IV or oral
melphalan should not be readministered since hypersensitivity reactions have
also been reported with oral melphalan.
12
<PAGE>
MISCELLANEOUS: Other reported adverse reactions include skin hypersensitivity,
skin ulceration at injection site, skin necrosis rarely requiring skin grafting,
vasculitis, alopecia, hemolytic anemia, allergic reaction, pulmonary fibrosis,
and interstitial pneumonitis.
OVERDOSAGE: Overdoses resulting in death have been reported. Overdoses,
including doses up to 290 mg/m2, have produced the following symptoms: severe
nausea and vomiting, decreased consciousness, convulsions, muscular paralysis,
and cholinomimetic effects. Severe mucositis, stomatitis, colitis, diarrhea, and
hemorrhage of the gastrointestinal tract occur at high doses (>100 mg/m2).
Elevations in liver enzymes and veno-occlusive disease occur infrequently.
Significant hyponatremia caused by an associated inappropriate secretion of ADH
syndrome has been observed. Nephrotoxicity and adult respiratory distress
syndrome have been reported rarely. The principal toxic effect is bone marrow
suppression. Hematologic parameters should be closely followed for 3 to 6 weeks.
An uncontrolled study suggests that administration of autologous bone marrow or
hematopoietic growth factors (i.e., sargramostim, filgrastim) may shorten the
period of pancytopenia. General supportive measures together with appropriate
blood transfusions and antibiotics should be instituted as deemed necessary by
the physician. This drug is not removed from plasma to any significant degree by
hemodialysis or hemoperfusion. A pediatric patient survived a 254-mg/m2 overdose
treated with standard supportive care.
DOSAGE AND ADMINISTRATION: The usual IV dose is 16 mg/m2. Dosage reduction of up
to 50% should be considered in patients with renal insufficiency (BUN =>30
mg/dL) (see PRECAUTIONS: General). The drug is administered as a single infusion
over 15 to 20 minutes. Melphalan is administered at 2-week intervals for 4
doses, then, after adequate recovery from toxicity, at 4-week intervals.
Available evidence suggests about one third to one half of the patients with
multiple myeloma show a favorable response to the drug. Experience with oral
melphalan suggests that repeated courses should be given since improvement may
continue slowly over many months, and the maximum benefit may be missed if
treatment is abandoned prematurely. Dose adjustment on the basis of blood cell
counts at the nadir and day of treatment should be considered.
ADMINISTRATION PRECAUTIONS: As with other toxic compounds, caution should be
exercised in handling and preparing the solution of ALKERAN. Skin reactions
associated with accidental exposure may occur. The use of gloves is recommended.
If the solution of ALKERAN contacts the skin or mucosa, immediately wash the
skin or mucosa thoroughly with soap and water.
Procedures for proper handling and disposal of anticancer drugs should be
considered. Several guidelines on this subject have been published.1-7 There is
no general agreement that all of the procedures recommended in the guidelines
are necessary or appropriate.
Parenteral drug products should be visually inspected for particulate matter
and discoloration prior to administration whenever solution and container
permit. If either occurs, do not use this product.
PREPARATION FOR ADMINISTRATION/STABILITY:
1. ALKERAN for Injection must be reconstituted by rapidly injecting 10 mL of
the supplied diluent directly into the vial of lyophilized powder using a
sterile needle (20-gauge or larger needle diameter) and syringe.
Immediately shake vial vigorously until a clear solution is obtained. This
provides a 5-mg/mL solution of melphalan. Rapid addition of the diluent
followed by immediate vigorous shaking is important for proper dissolution.
13
<PAGE>
2. IMMEDIATELY dilute the dose to be administered in 0.9% Sodium Chloride
Injection, USP, to a concentration not greater than 0.45 mg/mL.
3. Administer the diluted product over a minimum of 15 minutes. 4. Complete
administration within 60 minutes of reconstitution.
The time between reconstitution/dilution and administration of ALKERAN
should be kept to a minimum because reconstituted and diluted solutions of
ALKERAN are unstable. Over as short a time as 30 minutes, a citrate derivative
of melphalan has been detected in reconstituted material from the reaction of
ALKERAN with Sterile Diluent for ALKERAN. Upon further dilution with saline,
nearly 1% label strength of melphalan hydrolyzes every 10 minutes.
A precipitate forms if the reconstituted solution is stored at 5(Degree)C.
DO NOT REFRIGERATE THE RECONSTITUTED PRODUCT.
HOW SUPPLIED: ALKERAN for Injection is supplied in a carton containing one
single-use clear glass vial of freeze-dried melphalan hydrochloride equivalent
to 50 mg melphalan and one 10-mL clear glass vial of sterile diluent (NDC
0173-0130-93).
STORE AT CONTROLLED ROOM TEMPERATURE 15(DEGREE) TO 30(DEGREE)C (59(DEGREE)
TO 86(DEGREE)F) AND PROTECT FROM LIGHT.
REFERENCES:
1. Recommendations for the safe handling of parenteral antineoplastic drugs.
Washington, DC: Division of Safety, National Institutes of Health; 1983. US
Dept of Health and Human Services, Public Health Service publication NIH
83-2621.
2. AMA Council on Scientific Affairs. Guidelines for handling parenteral
antineoplastics. JAMA. 1985;253:1590-1591.
3. National Study Commission on Cytotoxic Exposure. Recommendations for
handling cytotoxic agents. 1987. Available from Louis P. Jeffrey, Chairman,
National Study Commission on Cytotoxic Exposure. Massachusetts College of
Pharmacy and Allied Health Sciences, 179 Longwood Avenue, Boston, MA 02115.
4. Clinical Oncological Society of Australia. Guidelines and recommendations
for safe handling of antineoplastic agents. Med J Australia.
1983;1:426-428.
5. Jones RB, Frank R, Mass T. Safe handling of chemotherapeutic agents: a
report from the Mount Sinai Medical Center. CA-A Cancer J for Clin.
1983;33:258-263.
6. American Society of Hospital Pharmacists. ASHP technical assistance
bulletin on handling cytotoxic and hazardous drugs. Am J Hosp Pharm.
1990;47:1033-1049.
7. Controlling Occupational Exposure to Hazardous Drugs. (OSHA Work-Practice
Guidelines.) Am J Health-Syst Pharm. 1996;53:1669-1685.
[GRAPHIC OMITTED]
GlaxoSmithKline
Research Triangle Park, NC 27709
Made in England
(C)2001, GlaxoSmithKline
All rights reserved.
November 2001 RL-1026
14
<page>
EXHIBIT 5.01 (CON'T.)
---------------------
PRODUCT INFORMATION
ALKERAN(R)
(melphalan)
Tablets
--------------------------------------------------------------------------------
WARNING: ALKERAN (melphalan) should be administered under the supervision of a
qualified physician experienced in the use of cancer chemotherapeutic agents.
Severe bone marrow suppression with resulting infection or bleeding may occur.
Melphalan is leukemogenic in humans.
Melphalan produces chromosomal aberrations in vitro and in vivo and, therefore,
should be considered potentially mutagenic in humans.
--------------------------------------------------------------------------------
DESCRIPTION: ALKERAN (melphalan), also known as L-phenylalanine mustard,
phenylalanine mustard, L-PAM, or L-sarcolysin, is a phenylalanine derivative of
nitrogen mustard. Melphalan is a bifunctional alkylating agent which is active
against selective human neoplastic diseases. It is known chemically as
4-[bis(2-chloroethyl)amino]-L-phenylalanine. The molecular formula is
C13H18Cl2N2O2 and the molecular weight is 305.20. The structural formula is:
[GRAPHIC OMITTED]
Melphalan is the active L-isomer of the compound and was first synthesized
in 1953 by Bergel and Stock; the D-isomer, known as medphalan, is less active
against certain animal tumors, and the dose needed to produce effects on
chromosomes is larger than that required with the L-isomer. The racemic (DL-)
form is known as merphalan or sarcolysin.
Melphalan is practically insoluble in water and has a pKa1 of ~2.5.
ALKERAN (melphalan) is available in tablet form for oral administration.
Each film-coated tablet contains 2 mg melphalan and the inactive ingredients
colloidal silicon dioxide, crospovidone, hypromellose, macrogol/PEG 400,
magnesium stearate, microcrystalline cellulose, and titanium dioxide.
CLINICAL PHARMACOLOGY: Melphalan is an alkylating agent of the
bischloroethylamine type. As a result, its cytotoxicity appears to be related to
the extent of its interstrand cross-linking with DNA, probably by binding at the
N7 position of guanine. Like other bifunctional alkylating agents, it is active
against both resting and rapidly dividing tumor cells.
PHARMACOKINETICS: The pharmacokinetics of ALKERAN after oral administration has
been extensively studied in adult patients. Plasma melphalan levels are highly
variable after oral dosing, both with respect to the time of the first
appearance of melphalan in plasma (range approximately 0 to 6 hours) and to the
peak plasma concentration (Cmax) (range 70 to 4000 ng/mL, depending upon the
dose) achieved. These results may be due to incomplete
15
<PAGE>
intestinal absorption, a variable "first pass" hepatic metabolism, or to rapid
hydrolysis. Five patients were studied after both oral and intravenous (IV)
dosing with 0.6 mg/kg as a single bolus dose by each route. The areas under the
plasma concentration-time curves (AUC) after oral administration averaged 61%
+/- 26% (+/- standard deviation [SD]; range 25% to 89%) of those following IV
administration. In 18 patients given a single oral dose of 0.6 mg/kg of ALKERAN,
the terminal elimination plasma half-life (t1/2) of parent drug was 1.5 +/- 0.83
hours. The 24-hour urinary excretion of parent drug in these patients was 10%
+/- 4.5%, suggesting that renal clearance is not a major route of elimination of
parent drug. In a separate study in 18 patients given single oral doses of 0.2
to 0.25 mg/kg of ALKERAN, Cmax and AUC, when dose adjusted to a dose of 14 mg,
were (mean +/- SD) 212 +/- 74 ng/mL and 498 +/- 137 ngoh/mL, respectively.
Elimination phase t1/2 in these patients was approximately 1 hour and the median
tmax was 1 hour.
One study using universally labeled 14C-melphalan, found substantially less
radioactivity in the urine of patients given the drug by mouth (30% of
administered dose in 9 days) than in the urine of those given it intravenously
(35% to 65% in 7 days). Following either oral or IV administration, the pattern
of label recovery was similar, with the majority being recovered in the first 24
hours. Following oral administration, peak radioactivity occurred in plasma at 2
hours and then disappeared with a half-life of approximately 160 hours. In one
patient where parent drug (rather than just radiolabel) was determined, the
melphalan half-disappearance time was 67 minutes.
The steady-state volume of distribution of melphalan is 0.5 L/kg.
Penetration into cerebrospinal fluid (CSF) is low. The extent of melphalan
binding to plasma proteins ranges from 60% to 90%. Serum albumin is the major
binding protein, while (alpha)1-acid glycoprotein appears to account for about
20% of the plasma protein binding. Approximately 30% of melphalan is
(covalently) irreversibly bound to plasma proteins. Interactions with
immunoglobulins have been found to be negligible.
Melphalan is eliminated from plasma primarily by chemical hydrolysis to
monohydroxymelphalan and dihydroxymelphalan. Aside from these hydrolysis
products, no other melphalan metabolites have been observed in humans. Although
the contribution of renal elimination to melphalan clearance appears to be low,
one pharmacokinetic study showed a significant positive correlation between the
elimination rate constant for melphalan and renal function and a significant
negative correlation between renal function and the area under the plasma
melphalan concentration/time curve.
INDICATIONS AND USAGE: ALKERAN Tablets are indicated for the palliative
treatment of multiple myeloma and for the palliation of non-resectable
epithelial carcinoma of the ovary.
CONTRAINDICATIONS: ALKERAN should not be used in patients whose disease has
demonstrated a prior resistance to this agent. Patients who have demonstrated
hypersensitivity to melphalan should not be given the drug.
WARNINGS: ALKERAN SHOULD BE ADMINISTERED IN CAREFULLY ADJUSTED DOSAGE BY OR
UNDER THE SUPERVISION OF EXPERIENCED PHYSICIANS WHO ARE FAMILIAR WITH THE DRUG'S
ACTIONS AND THE POSSIBLE COMPLICATIONS OF ITS USE.
As with other nitrogen mustard drugs, excessive dosage will produce marked
bone marrow suppression. Bone marrow suppression is the most significant
toxicity associated with ALKERAN in most patients. Therefore, the following
tests should be performed at the start of
16
<page>
therapy and prior to each subsequent course of ALKERAN: platelet count,
hemoglobin, white blood cell count, and differential. Thrombocytopenia and/or
leukopenia are indications to withhold further therapy until the blood counts
have sufficiently recovered. Frequent blood counts are essential to determine
optimal dosage and to avoid toxicity (see PRECAUTIONS: Laboratory Tests). Dose
adjustment on the basis of blood counts at the nadir and day of treatment should
be considered.
Hypersensitivity reactions, including anaphylaxis, have occurred rarely (see
ADVERSE REACTIONS). These reactions have occurred after multiple courses of
treatment and have recurred in patients who experienced a hypersensitivity
reaction to IV ALKERAN. If a hypersensitivity reaction occurs, oral or IV
ALKERAN should not be readministered.
CARCINOGENESIS: Secondary malignancies, including acute nonlymphocytic leukemia,
myeloproliferative syndrome, and carcinoma have been reported in patients with
cancer treated with alkylating agents (including melphalan). Some patients also
received other chemotherapeutic agents or radiation therapy. Precise
quantitation of the risk of acute leukemia, myeloproliferative syndrome, or
carcinoma is not possible. Published reports of leukemia in patients who have
received melphalan (and other alkylating agents) suggest that the risk of
leukemogenesis increases with chronicity of treatment and with cumulative dose.
In one study, the 10-year cumulative risk of developing acute leukemia or
myeloproliferative syndrome after melphalan therapy was 19.5% for cumulative
doses ranging from 730 mg to 9652 mg. In this same study, as well as in an
additional study, the 10-year cumulative risk of developing acute leukemia or
myeloproliferative syndrome after melphalan therapy was less than 2% for
cumulative doses under 600 mg. This does not mean that there is a cumulative
dose below which there is no risk of the induction of secondary malignancy. The
potential benefits from melphalan therapy must be weighed on an individual basis
against the possible risk of the induction of a second malignancy.
Adequate and well-controlled carcinogenicity studies have not been conducted
in animals. However, i.p. administration of melphalan in rats (5.4 to 10.8
mg/m2) and in mice (2.25 to 4.5 mg/m2) 3 times per week for 6 months followed by
12 months post-dose observation produced peritoneal sarcoma and lung tumors,
respectively.
MUTAGENESIS: ALKERAN has been shown to cause chromatid or
chromosome damage in humans. Intramuscular administration of ALKERAN at 6 and 60
mg/m2 produced structural aberrations of the chromatid and chromosomes in bone
marrow cells of Wistar rats.
IMPAIRMENT OF FERTILITY: ALKERAN causes suppression of ovarian function in
premenopausal women, resulting in amenorrhea in a significant number of
patients. Reversible and irreversible testicular suppression have also been
reported.
PREGNANCY: Pregnancy Category D. ALKERAN may cause fetal harm when administered
to a pregnant woman. Melphalan was embryolethal and teratogenic in rats
following oral (6 to 18 mg/m2 per day for 10 days) and intraperitoneal (18
mg/m2) administration. Malformations resulting from melphalan included
alterations of the brain (underdevelopment, deformation, meningocele, and
encephalocele) and eye (anophthalmia and microphthalmos), reduction of the
mandible and tail, as well as hepatocele (exomphaly).
There are no adequate and well-controlled studies in pregnant women. If this
drug is used during pregnancy, or if the patient becomes pregnant while taking
this drug, the patient should be apprised of the potential hazard to the fetus.
Women of childbearing potential should be advised to avoid becoming pregnant.
17
<PAGE>
PRECAUTIONS:
GENERAL: In all instances where the use of ALKERAN is considered for
chemotherapy, the physician must evaluate the need and usefulness of the drug
against the risk of adverse events. ALKERAN should be used with extreme caution
in patients whose bone marrow reserve may have been compromised by prior
irradiation or chemotherapy, or whose marrow function is recovering from
previous cytotoxic therapy. If the leukocyte count falls below 3000 cells/mcL,
or the platelet count below 100,000 cells/mcL, ALKERAN should be discontinued
until the peripheral blood cell counts have recovered.
A recommendation as to whether or not dosage reduction should be made
routinely in patients with renal insufficiency cannot be made because:
a) There is considerable inherent patient-to-patient variability in the
systemic availability of melphalan in patients with normal renal function.
b) Only a small amount of the administered dose appears as parent drug in the
urine of patients with normal renal function.
Patients with azotemia should be closely observed, however, in order to make
dosage reductions, if required, at the earliest possible time.
INFORMATION FOR PATIENTS: Patients should be informed that the major toxicities
of ALKERAN are related to bone marrow suppression, hypersensitivity reactions,
gastrointestinal toxicity, and pulmonary toxicity. The major long-term
toxicities are related to infertility and secondary malignancies. Patients
should never be allowed to take the drug without close medical supervision and
should be advised to consult their physician if they experience skin rash,
vasculitis, bleeding, fever, persistent cough, nausea, vomiting, amenorrhea,
weight loss, or unusual lumps/masses. Women of childbearing potential should be
advised to avoid becoming pregnant.
LABORATORY TESTS: Periodic complete blood counts with differentials should be
performed during the course of treatment with ALKERAN. At least one
determination should be obtained prior to each treatment course. Patients should
be observed closely for consequences of bone marrow suppression, which include
severe infections, bleeding, and symptomatic anemia (see WARNINGS).
DRUG INTERACTIONS: There are no known drug/drug interactions with oral ALKERAN.
CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY: See WARNINGS section.
PREGNANCY: TERATOGENIC EFFECTS: Pregnancy Category D: See WARNINGS section.
NURSING MOTHERS: It is not known whether this drug is excreted in human milk.
ALKERAN should not be given to nursing
mothers.
PEDIATRIC USE: The safety and effectiveness of ALKERAN in pediatric patients
have not been established.
GERIATRIC USE: Clinical experience with ALKERAN has not identified differences
in responses between the elderly and younger patients. In general, dose
selection for an elderly patient should be cautious, reflecting the greater
frequency of decreased hepatic, renal, or cardiac function, and of concomitant
disease or other drug therapy.
ADVERSE REACTIONS:
HEMATOLOGIC: The most common side effect is bone marrow suppression. Although
bone marrow suppression frequently occurs, it is usually reversible if melphalan
is withdrawn early enough. However, irreversible bone marrow failure has been
reported.
18
<PAGE>
GASTROINTESTINAL: Gastrointestinal disturbances such as nausea and vomiting,
diarrhea, and oral ulceration occur infrequently. Hepatic disorders ranging from
abnormal liver function tests to clinical manifestations such as hepatitis and
jaundice have been reported.
MISCELLANEOUS: Other reported adverse reactions include: pulmonary fibrosis and
interstitial pneumonitis, skin hypersensitivity, vasculitis, alopecia, and
hemolytic anemia. Allergic reactions, including rare anaphylaxis, have occurred
after multiple courses of treatment.
OVERDOSAGE: Overdoses, including doses up to 50 mg/day for 16 days, have been
reported. Immediate effects are likely to be vomiting, ulceration of the mouth,
diarrhea, and hemorrhage of the gastrointestinal tract. The principal toxic
effect is bone marrow suppression. Hematologic parameters should be closely
followed for 3 to 6 weeks. An uncontrolled study suggests that administration of
autologous bone marrow or hematopoietic growth factors (i.e., sargramostim,
filgrastim) may shorten the period of pancytopenia. General supportive measures,
together with appropriate blood transfusions and antibiotics, should be
instituted as deemed necessary by the physician. This drug is not removed from
plasma to any significant degree by hemodialysis.
DOSAGE AND ADMINISTRATION:
MULTIPLE MYELOMA: The usual oral dose is 6 mg (3 tablets) daily. The entire
daily dose may be given at one time. The dose is adjusted, as required, on the
basis of blood counts done at approximately weekly intervals. After 2 to 3 weeks
of treatment, the drug should be discontinued for up to 4 weeks, during which
time the blood count should be followed carefully. When the white blood cell and
platelet counts are rising, a maintenance dose of 2 mg daily may be instituted.
Because of the patient-to-patient variation in melphalan plasma levels following
oral administration of the drug, several investigators have recommended that the
dosage of ALKERAN be cautiously escalated until some myelosuppression is
observed in order to assure that potentially therapeutic levels of the drug have
been reached.
Other dosage regimens have been used by various investigators. Osserman and
Takatsuki have used an initial course of 10 mg/day for 7 to 10 days. They report
that maximal suppression of the leukocyte and platelet counts occurs within 3 to
5 weeks and recovery within 4 to 8 weeks. Continuous maintenance therapy with 2
mg/day is instituted when the white blood cell count is greater than 4000
cells/mcL and the platelet count is greater than 100,000 cells/mcL. Dosage is
adjusted to between 1 and 3 mg/day depending upon the hematological response. It
is desirable to try to maintain a significant degree of bone marrow depression
so as to keep the leukocyte count in the range of 3000 to 3500 cells/mcL.
Hoogstraten et al have started treatment with 0.15 mg/kg per day for 7 days.
This is followed by a rest period of at least 14 days, but it may be as long as
5 to 6 weeks. Maintenance therapy is started when the white blood cell and
platelet counts are rising. The maintenance dose is 0.05 mg/kg per day or less
and is adjusted according to the blood count.
Available evidence suggests that about one third to one half of the patients
with multiple myeloma show a favorable response to oral administration of the
drug.
One study by Alexanian et al has shown that the use of ALKERAN in
combination with prednisone significantly improves the percentage of patients
with multiple myeloma who achieve palliation. One regimen has been to administer
courses of ALKERAN at 0.25 mg/kg per day for 4 consecutive days (or, 0.20 mg/kg
per day for 5 consecutive days) for a total dose of 1 mg/kg per course. These 4-
to 5-day courses are then repeated every 4 to 6 weeks if the granulocyte count
and the platelet count have returned to normal levels.
19
<PAGE>
It is to be emphasized that response may be very gradual over many months;
it is important that repeated courses or continuous therapy be given since
improvement may continue slowly over many months, and the maximum benefit may be
missed if treatment is abandoned too soon.
In patients with moderate to severe renal impairment, currently available
pharmacokinetic data do not justify an absolute recommendation on dosage
reduction to those patients, but it may be prudent to use a reduced dose
initially. Epithelial Ovarian Cancer: One commonly employed regimen for the
treatment of ovarian carcinoma has been to administer ALKERAN at a dose of 0.2
mg/kg daily for 5 days as a single course. Courses are repeated every 4 to 5
weeks depending upon hematologic tolerance.
ADMINISTRATION PRECAUTIONS: Procedures for proper handling and disposal of
anticancer drugs should be considered. Several guidelines on this subject have
been published.1-7
There is no general agreement that all of the procedures recommended in the
guidelines are necessary or appropriate.
HOW SUPPLIED: ALKERAN is supplied as white, film-coated, round, biconvex tablets
containing 2 mg melphalan in amber glass bottles with child-resistant closures.
One side is engraved with "GX EH3" and the other side is engraved with an "A."
Bottle of 50 (NDC 0173-0045-35).
STORE IN A REFRIGERATOR, 2(DEGREE) TO 8(DEGREE)C (36(DEGREE) TO
46(DEGREE)F). PROTECT FROM LIGHT.
REFERENCES:
1. Recommendations for the safe handling of parenteral antineoplastic drugs.
Washington, DC: Division of Safety, National Institutes of Health; 1983. US
Dept of Health and Human Services, Public Health Service publication NIH
83-2621.
2. AMA Council on Scientific Affairs. Guidelines for handling parenteral
antineoplastics. JAMA. 1985;253:1590-1591.
3. National Study Commission on Cytotoxic Exposure. Recommendations for
handling cytotoxic agents. 1987. Available from Louis P. Jeffrey, Chairman,
National Study Commission on Cytotoxic Exposure. Massachusetts College of
Pharmacy and Allied Health Sciences, 179 Longwood Avenue, Boston, MA 02115.
4. Clinical Oncological Society of Australia. Guidelines and recommendations
for safe handling of antineoplastic agents. Med J Australia.
1983;1:426-428.
5. Jones RB, Frank R, Mass T. Safe handling of chemotherapeutic agents: a
report from the Mount Sinai Medical Center. CA-A Cancer J for Clin.
1983;33:258-263.
6. American Society of Hospital Pharmacists. ASHP technical assistance
bulletin on handling cytotoxic and hazardous drugs. Am J Hosp Pharm.
1990;47:1033-1049.
7. Controlling Occupational Exposure to Hazardous Drugs. (OSHA Work-Practice
Guidelines.) Am J Health-Syst Pharm. 1996;53:1669-1685.
[GRAPHIC OMITTED]
GlaxoSmithKline
Research Triangle Park, NC 27709
(C)2001, GlaxoSmithKline
All rights reserved.
November 2001 RL-1025
20
<PAGE>
EXHIBIT 5.02(c)
SEMI-ANNUAL SUPPLY SCHEDULE PROCEDURES
Attached hereto.
21
<PAGE>
EXHIBIT 5.04
Product Minimum Order Amounts
------- ---------------------
Alkeran IV 12,500 units
Alkeran Oral 25 mg bottles x 25 10,000 bottles
22
<PAGE>
EXHIBIT 5.08
ALKERAN MANUFACTURING MATRIX
----------------------------
The below table summarizes the Alkeran(R) manufacturing and packaging matrix for
the active drug substance and finished product. GlaxoSmithKline would retain
responsibility for manufacturing and packaging during the term of the
distribution agreement.
ALKERAN(R) Tablets and Injection Manufacturing Summary
Product Active Drug Finished Product
Substance
--------------------------------------------------------------------------------
Melphalan
Dartford, UK
Drug Aerojet, Rancho N/A
Cordova,
Substance California
--------------------------------------------------------------------------------
Alkeran(R) As above Dartford, UK
Tablets Heumann, Germany
(to be filed
6/2003)
--------------------------------------------------------------------------------
Alkeran(R) As above Dartford, UK
Injection --------
SP
Pharmaceutic
als,
Albuquerque,
NM (approval
received for
Diluent,
pending for
active with
target of
4/15/2003)
--------------------------------------------------------------------------------
23
<PAGE>
EXHIBIT 6.04
SAFETY MONITORING OF ALKERAN(R)
-------------------------------
SAFETY DATABASE
GSK will hold the international safety database of adverse events for the
Product.
CORE TEXT
The Core Text will be written and maintained by GSK.
ADVERSE EVENT REPORTING [AE]
GSK will be responsible for expedited reporting of AE reports to FDA.
Should Celgene receive any AE reports regarding the Product, such data will be
forwarded within seventy-two (72) hours by faxing the data to GCSP at
1-919-483-5404 or by calling the GSK Customer Response Center (CRC) at
1-888-825-5249. The CRC will forward all reports received to the appropriate
contact person in GCSP. GCSP will be responsible for appropriate follow-up of
all AE reports it receives.
PERIODIC REPORTING
The responsibility for compilation of Periodic Safety Update Reports (PSURs) and
FDA Periodic Reports for the Products will lie with GSK.
REGULATORY INQUIRIES
Celgene will inform GSK, as soon as possible, of any safety-related regulatory
inquiries regarding the Products and will co-operate in providing requested
information promptly.
GENERAL MANAGEMENT OF SAFETY
If either party becomes aware of a safety issue regarding the Products
(including sales discontinuance, product recalls), that party will alert the
other party as soon as possible. Supporting documentation will be sent as soon
as possible thereafter.
24
<PAGE>
Public statements by Celgene on the safety of the Products, which go beyond the
scope of the Core Text must, as far as practical, be approved by GSK before
publication.
CONTACTS
<TABLE>
<CAPTION>
<S> <C> <C>
--------------------------------------------------------------------------------------------------------
For General Inquiries Sandra Bettenhausen, Director GSK
Central Functions Group, 5 Moore Drive
Global Clinical Safety & RTP, NC 27709
Pharmacovigilance Telephone 919-483-5069
Fax 919-483-5404
Sandra.h.bettenhausen@gsk.com
--------------------------------------------------------------------------------------------------------
--------------------------------------------------------------------------------------------------------
For Spontaneous Cases Karen Dillinger, GSK
Manager PMG Case Handling Group, 5 Moore Drive
Global Clinical Safety & RTP, NC 27709
Pharmacovigilance Telephone 919-483-5065
Fax 919-483-5404
Karen.h.dillinger@gsk.com
--------------------------------------------------------------------------------------------------------
--------------------------------------------------------------------------------------------------------
Local Labeling Information Local GSK contact name Address, tel, fax, e-mail
Melissa Beaman, Manager
Labeling Policy
Phone (919) 483-9316
--------------------------------------------------------------------------------------------------------
--------------------------------------------------------------------------------------------------------
Core Safety Information Dr Jackie Brown CPM
Head of Clinical and Prescribing GlaxoSmithKline R&D
Information Management Greenford Road
Greenford
Middlesex
UB6 0HE
UK
e-mail: JTB43568@gsk.com
--------------------------------------------------------------------------------------------------------
</TABLE>
Matters regarding ADR Reporting Procedures, Overdoses and Pregnancy should be
addressed by GSK to the following Celgene individual:
Celgene Corporation
7 Powder Horn Drive
Warren, NJ 07050
Attention: Rose M. Rogan, M.D.
Facsimile No.: 732.271.4115
Telephone No.: 732.805.3913
25
<PAGE>
EXHIBIT 6.05
PROCEDURES FOR SUBMITTING MEDICAL INQUIRIES
-------------------------------------------
Medical inquiries regarding the Products shall be submitted by Celgene or
Physicians directly to GSK by calling the number below:
Submit all medical queries by calling 1-888-825-5249
26
<PAGE>
EXHIBIT 6.08
PROCEDURES FOR REPORTING PRODUCT COMPLAINTS
-------------------------------------------
Information to be supplied by Celgene to GSK, to the extent available, regarding
complaints relating to the Product:
o Name, address and phone number of caller/complainant
o Description of inquiry or complaint
o Product strength, size (e.g., xxmg, bottle of YY)
o Lot number, expiration date
o Name, address and phone number of person reporting/forwarding complaint
to Celgene (e.g. pharmacist) and sample availability information
o Name of Celgene representative forwarding information
o GSK Customer Response Center (CRC) at 1-888-825-5249.
o Note: the complaint sample should be returned to GSK for evaluation.
27
<PAGE>
EXHIBIT 8.02(g)(i)
PRODUCT RETURNS FOR 12-MONTHS ENDED 12/31/02
AND JANUARY AND FEBRUARY 2003
Alkeran
Product Returns
($000s)
--------------------------------------------------------------------------------
Sales Returns 2002 2003 2002 2003
Dollars Dollars Units Units
--------------------------------------------------------------------------------
January 259.8 52.3 2,722 191
--------------------------------------------------------------------------------
February 180.6 51.8 1,841 161
--------------------------------------------------------------------------------
March 141.2 -- 1,472 --
--------------------------------------------------------------------------------
April 119.9 -- 1,053 --
--------------------------------------------------------------------------------
May 295.9 -- 0 --
--------------------------------------------------------------------------------
June 282.9 -- 3,188 --
--------------------------------------------------------------------------------
July 222.2 -- 1,302 --
--------------------------------------------------------------------------------
August 219.7 -- 1,738 --
--------------------------------------------------------------------------------
September 142.9 -- 709 --
--------------------------------------------------------------------------------
October 196.4 -- 843 --
--------------------------------------------------------------------------------
November 80.9 -- 339 --
--------------------------------------------------------------------------------
December 50.4 -- 242 --
--------------------------------------------------------------------------------
Grand Total 2,192.6 52.3 15,447 191
--------------------------------------------------------------------------------
28
<PAGE>
EXHIBIT 8.02(g)(ii)
INDIRECT CHARGEBACK HISTORY FOR 12-MONTHS ENDED 12/31/02
AND JANUARY AND FEBRUARY 2003
--------------------------------------------------------------------------------
Alkeran
Indirect Chargeback History
($000s)
--------------------------------------------------------------------------------
2001 Actual 2002 Actual 2003 YTD
--------------------------------------------------------------------------------
Indirect 2,783.8 2,184.5 359.7
Chargebacks
--------------------------------------------------------------------------------
29