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SECURITIES AND EXCHANGE COMMISSION
WASHINGTON, D.C. 20549
FORM 10-Q/A
____________________
[x] QUARTERLY REPORT PURSUANT SECTION 13 or 15(d) OF THE SECURITIES EXCHANGE
ACT OF 1934
For the quarter ended June 30, 1996
[ ] TRANSACTION REPORT PURSUANT TO SECTION 13 or 15(d) OF THE SECURITIES
EXCHANGE ACT OF 1934
For the transition period from ___________ to _____________
Commission File No. 0-18728
INTERNEURON PHARMACEUTICALS, INC.
(exact name of registrant as specified in its charter)
Delaware 04-3047911
(State or other jurisdiction of (I.R.S. Employer Identification
incorporation or organization) Number)
One Ledgemont Center, 99 Hayden Avenue 02173
Lexington, Massachusetts (Zip Code)
(Address of principal executive offices)
Registrant's telephone number, including area code (617) 861-8444
(Former name, former address and former fiscal year, if changed since last
report): Not Applicable
Indicate by check whether the registrant (1) has filed all reports required to
be filed by Section 13 or 15(d) of the Securities Exchange Act of 1934 during
the preceding 12 months (or for such shorter periods that the registrant was
required to file such reports), and (2) has been subject to such filing
requirements for the past 90 days.
Yes X No
--- ---
Indicate the number of shares outstanding of each of the issuer's class of
common stock, as of the latest practicable date.
Class Outstanding at July 31, 1996:
Common Stock $.001 par value 40,899,343 shares
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SIGNATURES
Pursuant to the requirements of the Securities Exchange Act of 1934, the
registrant has duly caused this report to be signed on its behalf by the
undersigned thereunto duly authorized.
INTERNEURON PHARMACEUTICALS, INC.
By: /s/ Glenn L. Cooper
----------------------------------------
Glenn L. Cooper, M.D., President
and Chief Executive Officer
(Principal Executive Officer)
Date: December 10, 1996
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EXHIBIT INDEX
3.4 - Restated Certificate of Incorporation of Registrant (17)
3.5 - By-Laws of Registrant (1)
4.4 - Certificate of Designation establishing Series C Preferred
Stock (17)
4.6 - Form of Registrant Warrant issued in subsidiary private
placement (25)
4.7 - Form of Registrant Warrant to be issued to Paramount
Capital, Inc., D.H. Blair & Co., Inc. or designees (25)
10.5 (a) - Consultant and Non-competition Agreement between the
Registrant, Richard Wurtman, M.D. (34)
10.5 (b) - Consultant and Non-competition Agreement between
InterNutria, Inc. and Judith Wurtman, Ph.D. (34)
10.6 - Assignment of Invention and Agreement between Richard
Wurtman, M.D., Judith Wurtman and the Registrant (1)
10.7 - Management Agreement between the Registrant
and Lindsay Rosenwald, M.D. (1)
10.9(a) - Restated and Amended 1989 Stock Option Plan (7)
10.10 - Form of Indemnification Agreement (1)
10.11 - Restated Amendment to MIT Option Agreement (1)
10.12(a) - Patent and Know-How License Agreement between the
Registrant and Les Laboratoires Servier ("Servier") dated
February 7, 1990 ("License Agreement") (1)
10.12(b) - Revised Appendix A to License Agreement (1)
10.12(c) - Amendment Agreement between Registrant and Servier, Orsem
and Oril, Produits Chimiques dated November 19,1992(3)(12)
10.12(d) - Amendment Agreement dated April 28, 1993 between Registrant
and Servier (16)
10.12 (e) - Consent and Amendment Agreement among Servier, American Home
Products Corp. and Registrant. (34)
10.13 - Trademark License Agreement between the Registrant and
Orsem dated February 7, 1990 (1)
10.14 - Supply Agreement between the Registrant and Oril Products
Chimiques dated February 7, 1990 (1)(3)
10.15(a) - Form of Indemnification Agreement between the Registrant and
Alexander M. Haig, Jr. (1)
10.16 - Assignment of Invention by Richard Wurtman, M.D. (1)
10.22(a) - License Agreement dated January 15, 1993, as amended,
between the Registrant and Grupo Ferrer (3)(16)
10.25 - License Agreement between the Registrant and the
Massachusetts Institute of Technology (4)
10.28 - Letter Agreement between the Registrant and Bobby W.
Sandage, Jr., Ph.D. (7)
10.29 - Amended Lease dated December 12, 1991 for Registrant's
offices in Lexington, Massachusetts (7)
10.29(a) - First Amendment to Lease dated as of October 14, 1994
between Registrant and Ledgemont Realty Trust (25)
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10.30 - License Agreement dated January 1, 1992 between the Trustees
of Princeton University and the Registrant (3)(8)
10.31 - Research Agreement dated as of July 1, 1991 between the
Registrant and the Trustees of Princeton University (3)(8)
10.32 - Consulting Agreement dated as of July 1, 1991 between the
Registrant and Daniel Kahne, Ph.D. (3)(8)
10.33 - License Agreement dated January 28, 1992 between Ohio
University, The Castle Group, Inc. and Scimark Corporation
(assigned to Progenitor, Inc.) (3)(8)
10.34 - Sponsored Research Agreement between Scimark Corporation
(assigned to Progenitor, Inc.) and Ohio University (3)(8)
10.34(a) - Letter Amendment between Progenitor, Inc. and Ohio
University (18)
10.35 - Technology License Contract dated December 18, 1991 between
the Registrant and the Mayo Foundation for Medical
Education and Research (3) (8)
10.36 - Exclusive License Agreement dated February 24, 1992 between
the Registrant and Purdue Research Foundation (9)
10.37 - License Agreement dated as of February 15, 1992 between the
Registrant and Massachusetts Institute of Technology (9)
10.39 - Employment Agreement between Transcell Technologies, Inc.
and Elizabeth Tallet dated November 11, 1992 and Guarantee
by Registrant (13)
10.40 - Patent and Know-How Sublicense and Supply Agreement between
Registrant and American Cyanamid Company dated November 19,
1992 (3)(12)
10.41 - Equity Investment Agreement between Registrant and American
Cyanamid Company dated November 19, 1992 (12)
10.42 - Trademark License Agreement between Registrant and American
Cyanamid Company dated November 19, 1992 (12)
10.43 - Consent Agreement between Registrant and Servier dated
November 19,1992 (12)
10.45 - Agreement between Registrant and Parexel International
Corporation dated October 22, 1992 (as of July 21, 1992) (3)
(14)
10.46 - License Agreement dated February 9, 1993 between the
Registrant and Massachusetts Institute of Technology (3)(15)
10.47 - Sublease between Enichem America and Transcell Technologies,
Inc. including guarantee by the Registrant (15)
10.49 - License Agreement between Registrant and Elan Corporation,
plc dated September 9, 1993 (3)(18)
10.50 - License Agreement between Transcell Technologies, Inc. and
Princeton University dated October 14, 1993 (3)(18)
10.51 - Letter Agreement between the Registrant and Mark S. Butler
(18)
10.52 - License Agreement dated February 18, 1994 between Registrant
and Rhone- Poulenc Rorer, S.A. (20)
10.54 - Form of Purchase Agreement dated as of February 24, 1994
(20)
10.54(a) - Form of Amendment to Purchase Agreement (20)
10.55 - Patent License Agreement between Registrant and
Massachusetts Institute of Technology dated March 1, 1994
(20)
10.56 - License Agreement between Progenitor, Inc. and Albert
Einstein College of Medicine of Yeshiva University dated as
of February 1,1994 (20)
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10.57 - Employment Letter dated February 28, 1994 between the
Registrant and Thomas F. Farb (21)
10.58 - Master Equipment Lease including Schedules and Exhibits
between Phoenix Leasing and Registrant (agreements for
Transcell and Progenitor are substantially identical), with
form of continuing guarantee for each of Transcell and
Progenitor (22)
10.59 - Exhibit D to Agreement between Registrant and Parexel
International Corporation dated as of March 15, 1994 (3)(22)
10.60(a) - Acquisition Agreement dated as of May 13, 1994 among the
Registrant, Intercardia, Inc., Cardiovascular Pharmacology
Engineering Consultants, Inc. (CPEC), Myocor, Inc. and the
sellers named therein (23)
10.60(b) - Amendment dated June 15, 1994 to the Acquisition Agreement
(23)
10.61 - License Agreement dated December 6, 1991 between Bristol-
Myers Squibb and CPEC, as amended (3)(23)
10.61(a) - Letter Agreement dated November 18, 1994 between CPEC and
Bristol-Myers Squibb (25)
10.62 - Lease Agreement between Thomas R. Eggers and Progenitor,
Inc. dated as of November 1994 with Registrant guaranty
(25)
10.63 - Form of Stock Purchase Agreement dated December 15, 1994
(25)
10.64 - Form of Investor Rights Agreement among Progenitor,
Transcell, Registrant and each investor in the subsidiary
private placement (25)
10.64(a) - Form of Investor Rights Agreement among Intercardia, the
Registrant and each investor in the Intercardia private
placement (25)
10.65 - 1994 Long-Term Incentive Plan (25)
10.67 - Employment Agreement between Intercardia and Clayton I.
Duncan with Registrant guarantee (25)
10.67(a) - Amendment to Employment Agreement between Intercardia, Inc.
and Clayton I. Duncan (27)
10.68 - Interneuron Pharmaceuticals, Inc. 1995 Employee Stock
Purchase Plan, as amended (27)
10.69 - Office Lease, dated April 24, 1995 between Intercardia, Inc.
and Highwoods/ Forsyth Limited Partnership, with Registrant
Guaranty (27)
10.70 (a) - License and Collaboration Agreement by and between
Progenitor, Inc., and Chiron Corporation dated March 31,
1995 (3) (30)
10.71 - Securities Purchase Agreement dated June 2, 1995 between the
Registrant and Reliance Insurance Company, including Warrant
and exhibits (29)
10.72 - Sponsored Research and License Agreement dated as of May 1,
1995 between Progenitor and Novo Nordisk (3) (30)
10.73 - Form of Stock Purchase Agreement dated as of June 28, 1995
(31)
10.74 - Securities Purchase Agreement dated as of August 16, 1995
between the Registrant and BT Holdings (New York), Inc.,
including Warrant issued to Momint (nominee of BT Holdings)
(32)
10.75 - Stock Purchase Agreement dated as August 23, 1995 between
the Registrant and Paresco, Inc. (32)
10.76 - Stock Purchase Agreement dated as of September 15, 1995
between the Registrant and Silverton International Fund
Limited (32)
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10.77 - Subscription Agreement dated September 21, 1995, as of
August 31, 1995, including Registration Rights Agreement
between Registrant and GFL Advantage Fund Limited. (32)
10.78 - Contract Manufacturing Agreement dated November 20,1995
between Registrant and Boehringer Ingelheim Pharmaceuticals,
Inc. (3) (34)
10.79 - Development and Marketing Collaboration and License
Agreement between Astra Merck, Inc., Intercardia, Inc. and
CPEC, Inc., dated December 4, 1995. (33)
10.80 - Intercompany Services Agreement between Registrant and
Intercardia, Inc. (33)
10.81 - Asset Purchase Agreement dated November 14, 1995 among
Registrant, InterNutria, Inc., and Walden Laboratories, Inc.
(34)
10.82 - Employment Agreement between Registrant and Glenn L. Cooper,
M.D. dated April 30, 1996 effective as of May 13, 1996 (37)
10.83 - Copromotion Agreement effective June 1, 1996 between Wyeth-
Ayerst Laboratories and Interneuron Pharmaceuticals, Inc.
(3)
10.84 - Master Consulting Agreement between Interneuron
Pharmaceuticals, Inc. and Quintiles, Inc. dated July 12,
1996 (38)
10.85 - Amendment No. 1 dated July 12, 1996 to Master Consulting
Agreement between Interneuron Pharmaceuticals, Inc. and
Quintiles, Inc. dated July 12, 1996 (3)
23 - Consent of Coopers & Lybrand L.L.P. (34)
___________________________
(1) Incorporated by reference to the Registrant's registration statement on
Form S-1 (File No. 33-2408) declared effective on March 8, 1990.
(3) Confidential Treatment requested for a portion of this Exhibit.
(4) Incorporated by reference to the Registrant's Annual Report on Form 10-K
for the year ended September 30, 1990.
(7) Incorporated by reference to Post-Effective Amendment No. 2 to the
Registrant's registration statement on Form S-1 (File No. 33-32408) filed
December 18, 1991.
(8) Incorporated by reference to the Registrant's Quarterly Report on Form 10-Q
for the three months ended December 31, 1991.
(9) Incorporated by reference to the Registrant's Quarterly Report on Form 10-Q
for the three months ended March 31, 1992.
(12) Incorporated by reference to the Registrant's Form 8-K dated November 30,
1992.
(13) Incorporated by reference to Post-Effective Amendment No. 5 to the
Registrant's Registration Statement on Form S-1 (File No. 33-32408) filed
on December 21, 1992.
(14) Incorporated by reference to the Registrant's Annual Report on Form 10-K
for the fiscal year ended September 30, 1992.
(15) Incorporated by reference to the Registrant's Quarterly Report on Form 10-Q
for the three months ended December 31, 1992
(16) Incorporated by reference to the Registrant's Quarterly Report on Form 10-Q
for the six months ended March 31, 1993
(17) Incorporated by reference to the Registrant's Quarterly Report on Form 10-Q
for the nine months ended June 30, 1993
(18) Incorporated by reference to the Registrant's Annual Report on Form 10-K
for the fiscal year ended September 30, 1993
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(20) Incorporated by reference to the Registrant's Registration Statement on
Form S-3 or Amendment No. 1 (File no. 33-75826)
(21) Incorporated by reference to the Registrant's Form 8-K dated March 31, 1994
(22) Incorporated by reference to the Registrant's Quarterly Report on Form 10-Q
for the six months ended March 31, 1994
(23) Incorporated by reference to the Registrant's Form 8-K dated June 20, 1994
(25) Incorporated by reference to the Registrant's Annual Report on Form 10-K
for the fiscal year ended September 30, 1994
(27) Incorporated by reference to the Registrant's Quarterly Report on From 10-Q
for the six months ended March 31, 1995
(29) Incorporated by reference to the Registrant's Quarterly Report on Form 8-K
dated June 2, 1995
(30) Incorporated by reference to the Registrant's Quarterly Report on Form 8-K
dated May 16, 1995; Exhibit 10.70 (a) supersedes Exhibit 10.70.
(31) Incorporated by reference to Registrant's Quarterly Report on Form 10-Q for
the nine months ended June 30, 1995.
(32) Incorporated by referring to Registrant's Report on Form 8-K dated August
16, 1995.
(33) Incorporated by reference to Registration Statement filed on Form S-1 (No.
33-80219) by Intercardia, Inc. on December 8, 1995.
(34) Incorporated by reference to Registrant's Annual Report on Form 10-K for
the fiscal year ended September 30, 1995.
(36) Incorporated by reference to Amendment No. 1 to Registrant's Registration
Statement on Form S-3 (File No. 333-1273) filed March 15, 1996.
(37) Incorporated by reference to Registrant's Registration Statement on Form
S-3 (File No. 333-03131) filed May 3, 1996
(38) Incorporated by reference to Registrant's Quarterly Report on Form 10-Q
for the nine months ended June 30, 1996
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Portions of this Exhibit have been omitted pursuant to a request for
confidential treatment. The omitted portions, marked by a * and [ ], have
been separately filed with the Commission.
COPROMOTION AGREEMENT
This Copromotion Agreement effective June 1, 1996, between WYETH-AYERST
LABORATORIES, 555 E. Lancaster Avenue, St. Davids, PA 19087 ("Wyeth-Ayerst")
and INTERNEURON PHARMACEUTICALS, INC., One Ledgemont Center, 99 Hayden Avenue,
Suite 340, Lexington, MA 02173(" Interneuron ").
WHEREAS, Interneuron has granted Wyeth-Ayerst exclusive patent and know-how
licenses to make, have made, use and sell finished pharmaceuticals containing
dexfenfluramine hydrochloride ("REDUX") for the treatment of obesity in the
United States. its territories and possessions and the Commonwealth of Puerto
Rico (the "Territory") pursuant to Patent and Know-How Sublicense and Supply
Agreement effective as of November 19, 1992, (the "Sublicense Agreement") as
amended pursuant to Consent and Amendment Agreement effective as of November 21,
1994 (the "Amendment Agreement"); and
WHEREAS, pursuant to Paragraph 6.4.2 of the Sublicense Agreement,
Interneuron retained copromotion rights to REDUX in the Territory, the details
of such copromotion, including the practitioner categories to whom Interneuron
would promote REDUX to be agreed to by Wyeth-Ayerst and Interneuron;
NOW, THEREFORE, in consideration of the foregoing and the mutual promises
and covenants herein contained, it is hereby agreed as follows:
1. Definitions
When used in this Agreement, the following terms shall have the following
respective meanings:
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The information below marked by * and [ ] has been omitted pursuant to a request
for confidential treatment. The omitted portion has been separately filed with
the Commission.
(a) "Contract Month" shall mean each one month period during the term of
this Agreement beginning June 1, 1996.
(b) "Contract Quarter" shall mean each three month period during the term
of this Agreement beginning June 1, 1996, provided, however the First Contract
Quarter shall end June 30, 1996.
(c) "Contract Year" shall mean each one year period during the term of this
Agreement beginning June 1, 1996.
(d) "Copromotion" shall mean those activities normally undertaken by a
pharmaceutical company's sales force to implement marketing plans and strategies
aimed at encouraging the appropriate use of a particular prescription
pharmaceutical product.
(e) "Detail" shall mean a one-on-one, face-to-face meeting, in an
individual or group practice setting, between one or more physician prescribers
and one Interneuron professional representative during which product information
is communicated that is in addition to any discussion regarding the physician's
sample needs. When used as a verb, "Detail" shall mean to engage in a Detail.
(f) "First Position Detail" shall mean [__________________________________]
(9) "REDUX Sales Force" shall mean up to thirty-three (33) regular, full-
time employees of Interneuron, thirty (30) of whom shall be employed and trained
as professional representatives to Detail REDUX to the Interneuron Categories
and three (3) of whom shall provide field sales management for the REDUX Sales
Force.
(h) "Sample" shall mean a unit of REDUX that is not intended to be sold and
is intended to promote the sale of REDUX.
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The information below marked by * and [ ] has been omitted pursuant to a request
for confidential treatment. The omitted portion has been separately filed with
the Commission.
2. COPROMOTION BY INTERNEURON
Interneuron shall copromote REDUX in the Territory by causing its REDUX
Sales Force to Detail to individual physicians, and small group practices of
physicians, who are bariatricians, nutritionists, full time-weight management
specialists, endocrinologists and diabetologists (the "Interneuron Categories").
Attached hereto as Exhibit A is an electronic list of physicians and small group
practices which shall constitute the candidates in the Interneuron Categories.
Exhibit A shall be periodically updated by mutual agreement of the parties.
The Interneuron Categories shall not include national and regional weight
loss organizations, e.g. NutriSystems, Weight Watchers, etc., which offer
multiple weight loss approaches and/or where physician supervised weight loss is
not the primary intervention. Physicians with multi-location offices or clinics
shall not PER SE be considered to be excluded as national or regional weight
loss organizations.
Physicians who Wyeth-Ayerst actively Details (defined as four (4) calls in
the previous twelve (12) months) on the effective date hereof may be excluded
from the Interneuron Categories.
[_______________________________________________________________________________
_____________]
3. DETAILING ADDITIONAL WYETH-AYERST PRODUCTS
During the first two (2) Contract Years, the REDUX Sales Force shall, if
Wyeth-Ayerst in its sole discretion so requests, Detail to the Interneuron
Categories additional
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The information below marked by * and [ ] has been omitted pursuant to a request
for confidential treatment. The omitted portion has been separately filed with
the Commission.
Wyeth-Ayerst products at the time of Details for REDUX. Wyeth-Ayerst shall
provide promotional materials and samples to Interneuron at no cost for such
detailing. Upon mutual agreement, physicians other than those in the
Interneuron Categories may be detailed by the REDUX Sales Force hereunder. For
detailing additional Wyeth-Ayerst products in the first Contract Year,
Interneuron shall receive no compensation other than the Interneuron sales force
subsidy provided in Section 4(a). For such additional detailing in the second
Contract Year, Wyeth-Ayerst shall pay Interneuron [$___] per full product
Detail.
4. INTERNEURON SALES FORCE SUBSIDY AND PROFIT SHARING
(a) SALES FORCE SUBSIDY. For the first two (2) Contract Years, Wyeth
Ayerst shall pay the following percentages of Interneuron's actual REDUX Sales
Force costs:
Year 1 - 100%
Year 2 - 50%
Provided, however, that the REDUX Sales Force shall not exceed thirty-three (33)
regular, full-time employees and Wyeth-Ayerst's payment obligation shall be
based on the above percentages of Interneuron actual REDUX Sales Force costs,
including, but not limited to, payroll, fringe benefits, travel expenses, sales
training costs, commissions and bonuses documented by Interneuron to Wyeth-
Ayerst's reasonable satisfaction, not in excess of [$_____________] per
representative per Contract Year. Interneuron shall provide Wyeth-Ayerst within
ten (10) days of the end of each Contract Month a monthly schedule of REDUX
Sales Force expenses along with a roster of sales people setting
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The information below marked by * and [ ] has been omitted pursuant to a request
for confidential treatment. The omitted portion has been separately filed with
the Commission.
forth their dates of hire. Within thirty (30) days of receipt of such schedule,
Wyeth-Ayerst will pay the amount provided for herein.
(b) PROFIT SHARING. For the first three (3) Contract Years, Wyeth-Ayerst
shall pay Interneuron the following percentages of REDUX Brand Profit, as
defined below, by physician category, for physicians or small groups in the
Interneuron Categories detailed by the REDUX Sales Force at least [_________]
times each Contract Year:
Bariatricians
Nutritionists Endocrinologists
Weight Mgt. Specialists Diabetologists
----------------------- --------------
Year 1 [______________________________]
Year 2 [______________________________]
Year 3 [______________________________]
Profit shall mean REDUX Net Sales (including any and all sales of REDUX by
Wyeth-Ayerst made prior to June 1, 1996) in the Interneuron Categories less cost
of goods sold, distribution costs, the costs of detail aids and other
promotional materials and samples for the REDUX Sales Force and allocated costs
for direct advertising and promotion expenses. REDUX Net Sales shall mean the
gross amount invoiced for REDUX less transportation charges or allowances, if
any, included in such price; trade, quantity or cash discounts, service
allowances and broker's or agent's commissions, if any, allowed or paid; credits
or allowances, if any, given or made on account of price adjustments, returns,
bad debts (actual write-offs only), off-invoice promotional discounts, rebates,
any and all federal, state or local government rebates whether in existence now
or enacted at any time during the Term of this Agreement (e.g. HCFA or
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The information below marked by * and [ ] has been omitted pursuant to a request
for confidential treatment. The omitted portion has been separately filed with
the Commission.
Medicaid rebates), rejections, recalls or REDUX destruction (voluntarily made or
requested or made by an appropriate government agency, sub-division or
department); and any tax, excise or governmental charge upon or measured by the
production, sale, transportation, delivery, or use of REDUX. Net Sales shall be
measured for the Interneuron Categories by utilizing the Xponent Rx database
supplemented by additional data sources appropriate in Wyeth-Ayerst's reasonable
judgment to accurately measure direct and indirect sales to dispensing
physicians in the Interneuron Categories. The above listed deductions from Net
Sales used to compute Profit hereunder shall be at cost. No intercompany
transfer profit shall be considered in calculating Profit hereunder. All
expenses considered under this profit sharing calculation will be applied using
Generally Accepted Accounting Principals ("GAAP"). Direct marketing expenses
shall not include internal overheads. Cost of goods sold and distribution
expenses for Redux are currently estimated to average [____%] of Net Sales.
Direct advertising and promotion expenses will be allocated based on Net Sales.
(c) MAXIMUM INTERNEURON COMBINED SALES FORCE SUBSIDY AND PROFIT SHARING.
Wyeth-Ayerst's combined sales force subsidy and profit sharing payments to
Interneuron shall not exceed $10,000,000 in any Contract Year.
(d) Profit sharing payments to Interneuron under this Section shall be
made on a Contract Quarter basis within [______________] days of the end of each
Contract Quarter together with supporting calculations. If the IMS data base is
not available to be used for the profit sharing calculation, Wyeth will use
reasonable estimates based on historical sales to perform the required profit
sharing calculation. [_______] percent of
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each quarterly payment for the first three (3) Contract Quarters of each
Contract Year shall be retained by Wyeth-Ayerst and remitted, as adjusted, with
the payment for the Fourth Contract Quarter which shall reflect all adjustments
to the sales force subsidy and profit sharing payments to Interneuron for the
Contract Year.
5. MARKETING, PRICING AND SALES FORCE
(a) Wyeth-Ayerst shall have the sole authority for the pricing,
marketing strategy and tactics for REDUX. All promotional and detailing
materials shall be supplied by Wyeth-Ayerst and not by Interneuron. The
determination of the content, the quantity, and the method of distribution of
the promotional materials and literature related to REDUX shall be the sole
responsibility of Wyeth-Ayerst. In connection with the Copromotion of REDUX,
Interneuron shall use only promotional materials and literature provided by
Wyeth-Ayerst, which shall be used only for the purposes of this Agreement and
shall be returned to Wyeth-Ayerst upon termination of this Agreement. All
copyright and other intellectual property rights therein shall remain vested in
Wyeth-Ayerst.
(b) Interneuron's REDUX Sales Force shall remain exclusively under the
authority of the field sales management of Interneuron. Interneuron shall have
full responsibility for the dissemination, of information regarding REDUX to its
REDUX Sales Force based on information provided by Wyeth-Ayerst.
(c) Wyeth-Ayerst shall have the sole right and responsibility for
establishing and modifying the terms and conditions with respect to the sale of
REDUX, including any terms and conditions relating to or affecting the price at
which REDUX will be sold,
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<PAGE>
any discount attributable to payments on receivables, distribution of REDUX,
credit to be granted or refused and the like.
(d) Wyeth-Ayerst shall inform Interneuron of list price increases or
decreases for REDUX in the Territory at the time such information is provided to
Wyeth-Ayerst's sales force.
(e) Wyeth-Ayerst shall be exclusively responsible for accepting and
filling purchase orders, billing, and returns with respect to REDUX. If
Interneuron receives an order for REDUX, it shall make best efforts to, within
forty-eight (48) hours, transmit such order to Wyeth-Ayerst for acceptance or
rejection, which acceptance or rejection shall be at Wyeth-Ayerst's sole
discretion. REDUX Net Sales in the final Contract Year of the term or any
extended term of this Agreement shall include sales made on all orders received
prior to the end of such Contract Year regardless of the date of acceptance or
fulfillment of such orders by Wyeth-Ayerst.
(f) The appointment of Interneuron hereunder, shall not create a joint
venture, or an employer-employee relationship or a principal-agent relationship
other than as specifically provided in this Agreement or in the Sublicense
Agreement or Amendment Agreement.
(g) Nothing in this Agreement shall be deemed to authorize Interneuron to
act for, represent, or bind Wyeth-Ayerst or any of its affiliates other than as
specifically provided by this Agreement.
(h) Neither party shall have any responsibility for the hiring,
termination, compensation or benefits of the other party's employees. No
employee or representative of a party shall have an authority to bind or
obligate the other party
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<PAGE>
The information below marked by * and [ ] has been omitted pursuant to a request
for confidential treatment. The omitted portion has been separately filed with
the Commission.
to this Agreement for any sum or in any manner whatsoever, or to create or
impose any contractual or other liability on the other party without said
party's authorized written approval.
6. TERM AND TERMINATION
(a) The initial term of this Agreement, unless sooner terminated
hereunder, shall be for three (3) years from June 1, 1996. Wyeth-Ayerst shall
have the option of extending the Agreement for one (1) or two (2) years
following the initial term on terms and conditions to be agreed upon by the
parties, provided that Wyeth-Ayerst shall give Interneuron three (3) months
prior written notice of any such extension. Interneuron may elect not to
copromote REDUX for an extended one (1) or two (2) year term.
(b) Either party may terminate this Agreement on thirty (30) days prior
written notice if the other party is in default and such default has not been
cured within thirty (30) days of such notice. Wyeth-Ayerst may terminate this
Agreement on thirty (30) days notice if REDUX is withdrawn from the market and
on ninety (90) days notice if total REDUX sales do not exceed [____] million in
any Contract Year or if Interneuron generated sales do not exceed [____] million
in any Contract Year. Interneuron may terminate at any time on six (6) months
notice. Upon notice of termination by either Wyeth-Ayerst or Interneuron,
Wyeth-Ayerst may immediately begin to phase in its own detailing to the
physicians Interneuron is calling on.
7. NONCOMPETITION
During the first eighteen (18) months of this Agreement, the REDUX Sales
Force will not promote another company's product. Thereafter, the REDUX Sales
Force will
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<PAGE>
not promote another company's product without Wyeth-Ayerst's prior consent which
shall not be unreasonably withheld. Such consent is conditioned on the products
not being a weight loss product; not being competitive with other Wyeth-Ayerst
products, and that REDUX remain in First Position Detail with full product
presentation for the entire term of this Agreement.
Interneuron shall not promote another anti-obesity drug during the term of
this Agreement. This provision is not intended to preclude Interneuron's
copromotion of other anti-obesity drugs for Wyeth-Ayerst nor does it grant
rights to Interneuron to do so. Interneuron shall not promote another anti-
obesity prescription drug product for one year following expiration of this
Agreement or one year following termination by Wyeth-Ayerst because of default
by Interneuron or termination by Interneuron except for default by Wyeth-Ayerst.
8. SAMPLES
(a) Samples of REDUX, to be used by Interneuron only for sampling to
Interneuron Categories, shall be sent to Interneuron at an agreed upon site and
at Wyeth-Ayerst's expense when REDUX has been descheduled as a controlled
substance. The storage and distribution of such Samples to the REDUX Sales
Force shall be at Interneuron's expense. Storage and distribution of such
Samples by Interneuron and sampling by the REDUX Sales Force shall be in
compliance with all federal, state and local laws and regulations and Wyeth-
Ayerst procedures concerning prescription drug samples, including but not
limited to, all laws concerning sample accountability. Wyeth-Ayerst shall have
the right to audit Interneuron's compliance with the above-referenced laws and
regulations upon reasonable notice and at reasonable
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times not to exceed twice a Contract Year. For purposes of this article, such
audit may, at Wyeth-Ayerst's option, be conducted by either Wyeth-Ayerst's
employees or consultants.
(b) The decision to sample shall be determined by Wyeth-Ayerst, the
quantity of Samples to be provided to Interneuron and the method of
distribution, including any limitations thereon, shall be determined jointly by
the parties.
(c) Interneuron shall, within sixty (60) days of the end of each Contract
Quarter during the term of this Agreement, provide to Wyeth-Ayerst a summary
analysis of the number of Samples distributed to Interneuron Categories during
the Contract Quarter.
(d) Interneuron shall be an Authorized Distributor of Record for REDUX for
purposes of the requirements of the Prescription Drug Marketing Act of 1987 (the
"PDMA") and shall comply with the PDMA, FDA regulations and applicable state law
requirements regarding the marketing, sale and distribution of REDUX, including
but not limited to applicable wholesale drug distribution licensing guidelines
and requirements.
(e) Interneuron shall establish and adhere to written procedures to assure
that Interneuron and the REDUX Sales Force comply with all requirements of the
PDMA. For this purpose, Wyeth-Ayerst shall provide for each REDUX Sales Force
employee a copy of the Wyeth-Ayerst Sample Accountability Manual, the receipt of
which shall be acknowledged and compliance agreed to by each such REDUX Sales
Force employee. Interneuron shall notify Wyeth-Ayerst immediately upon learning
that any REDUX Samples shipped by Wyeth-Ayerst to Interneuron have been lost or
have not been received as scheduled. In the event that Interneuron or any of
the REDUX Sales Force
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<PAGE>
fails to comply or causes Wyeth-Ayerst to fail to comply with applicable legal
requirements and as a direct result a civil penalty is assessed against Wyeth-
Ayerst or any of its affiliates or employees, then Interneuron shall hold
harmless and indemnify Wyeth-Ayerst, its affiliates or its employees from any
such civil penalty or other damages or losses related thereto, including
reasonable attorneys' fees unless such failure was caused by Wyeth-Ayerst.
9. ADVERSE REACTION REPORTING AND REGULATORY MATTERS
(a) Interneuron shall notify Wyeth-Ayerst within twenty-four (24)
hours if Interneuron receives any notice of a serious or unexpected adverse drug
experience associated with the use of REDUX. The terms "serious," "unexpected,"
and "adverse drug experience" as used in this Section 9(a) shall have the same
meaning as the definitions set forth in Title 21 of the Code of Federal
Regulations, Section 314.80(a), and in effect at the time of Interneuron's
notice of report to Wyeth-Ayerst. Interneuron shall notify Wyeth-Ayerst
immediately upon receiving notice of (1) information concerning any incident
that causes REDUX or its labeling to be mistaken for, or applied to, another
article; or (2) information concerning any change or deterioration in REDUX.
Any repeated failure to notify Wyeth-Ayerst under this provision shall be
grounds for termination, at Wyeth-Ayerst's option.
(b) Interneuron shall report monthly to Wyeth-Ayerst all other
significant information concerning any complaint of any kind regarding REDUX,
its labeling, quality or packaging, including but not limited to, any adverse
drug experience not reported pursuant to Section 9(a) above.
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(c) It is understood and agreed that the reporting requirements set
forth in this Section 9 are based on Wyeth-Ayerst policies and procedures and
regulatory reporting requirements. Accordingly, in the event of changes to
regulatory requirements or Wyeth-Ayerst policies and procedures for adverse
experience reporting, Interneuron agrees to comply with all reasonable revised
notification procedures as requested in writing by Wyeth-Ayerst.
(d) Wyeth-Ayerst shall evaluate all adverse drug experiences
associated with REDUX, including those reported to Wyeth-Ayerst by Interneuron,
and appropriately report serious or unexpected adverse drug experiences to FDA.
10. RETURN/RECALL
(a) Any REDUX returned to Interneuron shall be shipped to Wyeth-
Ayerst's nearest facility, with any reasonable or authorized shipping or other
documented direct cost to be paid by Wyeth-Ayerst. Interneuron shall incur no
liability of any nature in the handling of such returns. Interneuron, at its
option, may advise the customer who made the return that the REDUX has been
returned to Wyeth-Ayerst.
(b) At Wyeth-Ayerst's request, Interneuron shall reasonably assist
Wyeth-Ayerst in obtaining and receiving REDUX that has been recalled, and any
direct documented costs incurred by Interneuron with respect to participating in
such recall shall be reimbursed by Wyeth-Ayerst.
11. FORCE MAJEURE
Neither of the parties shall be liable or be in breach of any provision of
this Agreement for any failure or omission on its part to perform any
obligations because of force majeure, including, but not limited to war, riot,
fire, explosion, flood, sabotage,
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accident or breakdown of machinery; unavailability of fuel, labor, containers or
transportation facilities; accidents of navigation or breakdown or damages of
vessels. or other conveyances for air, land or sea; other impediments or
hindrances to transportation; strike or other labor disturbances; governmental
regulation, or any other cause beyond the reasonable control of the party; and
provided that such failure or omission resulting from one of the above causes is
cured as soon as practicable after the occurrence of one or more of the
abovementioned causes.
12. RECORD AND AUDIT PROVISIONS
Each party shall keep accurate records in sufficient detail (a) Interneuron
of the number of Details and the positioning of such Details for REDUX and other
information regarding all Details for REDUX or additional Wyeth-Ayerst products
and (b) Wyeth-Ayerst of the financial computations required to make payments to
Interneuron which are required under this Agreement. Each party, upon
reasonable advance notice to the other party, and at the requesting party's
expense, shall permit an independent, certified public accountant of the
requesting party, except one to whom the other party has reasonable objections,
to have access during ordinary business hours to the other party's records which
pertain to the performance of this Agreement. Such examination shall not take
place more than twice a Contract Year during the term of this Agreement. These
requests with respect to any year shall terminate two (2) years after the end of
such year.
13. WARRANTY AND INDEMNITY
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(a) Each party warrants and represents to the other that it has the
full right and authority to enter into this Agreement, and that it is not aware
of any impediment that would inhibit its ability to perform its obligations
under this Agreement.
(b) Wyeth-Ayerst shall indemnify, defend, and hold Interneuron
harmless from any claims, damages, actions, liabilities, losses, costs and
expenses, including reasonable attorneys' fees, (hereinafter "Claims") of a
third party, arising from the promotion of REDUX by Wyeth-Ayerst in violation of
approved labeling or any applicable statute or regulation, or any breach by
Wyeth-Ayerst of its obligations under this Agreement unless such Claims arise
from a manufacturing or design defect of REDUX, Interneuron's breach of its
responsibilities under this Agreement or a negligent or wrongful act of
Interneuron. Interneuron shall notify Wyeth-Ayerst immediately of any such
Claims and shall cooperate with Wyeth-Ayerst in the defense of such Claims.
(c) Interneuron shall indemnify and hold Wyeth-Ayerst harmless from
any Claims of a third party arising out of the storage and distribution of REDUX
or Samples of REDUX by Interneuron, the Copromotion of REDUX by Interneuron in
violation of approved labeling or any applicable statute or regulation, any
breach by Interneuron of its obligations under the Agreement, a manufacturing or
design defect of REDUX, unless such Claims arise from Wyeth-Ayerst's breach of
its responsibilities under this Agreement, or a negligent or wrongful act of
Wyeth-Ayerst. Wyeth-Ayerst shall notify Interneuron immediately of any such
claim, damage or loss and shall cooperate with Interneuron in the defense of
such Claims.
(d) Each party agrees to give the other prompt written notice of any
Claims made for which the other might be liable under the foregoing
indemnification
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together with the opportunity to defend, negotiate, and settle such Claims. The
party seeking indemnification under this Agreement shall provide the other party
with all information in its possession, authority, and assistance necessary to
enable the indemnifying party to carry on the defense of such Claims. Neither
party shall be responsible or bound by any settlement made without its prior
written consent.
13. WAIVER/MODIFICATION
Any term or condition of this Agreement may be waived or modified at any
time by the party entitled to the benefit thereof by a written instrument
executed by both parties. No delay or failure on the part of any party in
exercising any rights hereunder and no partial or single exercise thereof, will
constitute a waiver of such rights or of any rights hereunder.
14. GOVERNING LAW
This Agreement shall be construed and the respective rights of the parties
hereto determined according to the substantive laws of the State of New Jersey
notwithstanding the provisions to the contrary governing conflict of laws under
such law.
15. SEVERANCE
If any one or more of the provisions of this Agreement shall be held to be
invalid, illegal or unenforceable, the validity, legality or enforceability of
the remaining provisions hereof shall not in any way be affected or impaired
thereby. To the extent permitted by applicable law, each party waives any
provision of law which renders any provision hereof invalid, illegal or
unenforceable in any respect. In the event any provision of this Agreement
shall be held to be invalid, illegal or unenforceable, the parties hereto shall
negotiate in good faith to substitute a valid, legal and enforceable provision
which, insofar as practical, implements the purposes hereof.
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16. ENTIRE AGREEMENT
This Agreement contains the entire agreement between the parties in respect
of the subject matter hereof and supersedes and cancels all previous agreements,
negotiations, commitments and writings between the parties hereto with respect
to the subject matter hereof and may not be changed or modified in any manner or
released, discharged, abandoned or otherwise terminated unless in writing and
signed by the duly authorized officers or representatives of the parties.
17. NOTICE
Any notice or request required or permitted to be given in connection with
this Agreement shall be deemed to have been sufficiently given if sent by
prepaid registered mail or telecopier to the intended recipient as set forth
below or such other business address as may have been furnished in writing by
the intended recipient to the sender. The date of mailing or telecopying shall
be deemed to be the effective date on which notice was given, provided that all
telecopies shall have been confirmed either electronically or by the intended
recipient if such confirmation is received within twenty-four (24) hours of its
transmission.
WYETH-AYERST
Joseph M. Mahady, President
Pharmaceutical Division
with copy to:
Charles N. Ross, Esq., Director
Legal Division
INTERNEURON
Glenn L. Cooper, M.D., President and Chief Executive Officer
with copy to:
Mark S. Butler, Esq.,
Executive Vice President and
Chief Administrative Officer
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18. PUBLIC ANNOUNCEMENTS
Any public announcements or publicity with respect to this Agreement or the
transaction contemplated herein shall be at such time and in such manner as
Wyeth-Ayerst and Interneuron shall agree, provided that nothing herein shall
prevent either party, following notice and opportunity to review by the other,
from making such public announcements as such party's legal obligations require.
19. SUPREMACY OF SUBLICENSE AGREEMENT
Nothing in this Agreement: shall in any way supersede, alter or diminish
any rights either of the parties may have under the Sublicense Agreement.
IN WITNESS WHEREOF, the parties have caused this Agreement to be executed
by the duly authorized officers effective as of June 1, 1996.
WYETH-AYERST LABORATORIES
By: /s/ Joseph M. Mahady
---------------------------
Name: Joseph M. Mahady
Title: President, Pharmaceutical Division
INTERNEURON PHARMACEUTICALS INC.
By: /s/ Mark S. Butler
---------------------------
Name: Mark S. Butler
Title: EVP
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<PAGE>
The information below marked by * and [ ] has been omitted pursuant to a request
for confidential treatment. The omitted portion has been separately filed with
the Commission.
EXHIBIT A
[
]
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<PAGE>
Exhibit 10.85
Portions of this Exhibit have been omitted pursuant to a request for
confidential treatment. The omitted portions, marked by a * and [ ], have
been separately filed with the Commission.
AMENDMENT NO. 1 TO MASTER CONSULTING AGREEMENT
The Master Consulting Agreement, by and between Interneuron and Quintiles,
consisting of one (1) page, dated 3 July, 1996, is hereby amended as follows:
(1) The following Attachments shall be made a part of the Master Consulting
Agreement, to wit:
ATTACHMENT NO. 1
SCOPE OF WORK (PROTOCOL NO. [_________]) *
ATTACHMENT NO. 2
PROJECT BUDGET (PROTOCOL NO. [_________]) *
ATTACHMENT NO. 3
PAYMENT SCHEDULE (PROTOCOL NO. [_________]) *
QUINTILES, INC. INTERNEURON PHARMACEUTICALS
BY /s/ K.A. WILLIAMS BY /s/ GLENN L. COOPER
---------------------------- ----------------------------
K. A. WILLIAMS, DR. P.H.
VICE PRESIDENT, TITLE PRESIDENT
CONTRACTS MANAGEMENT & PLANNING -------------------------
DATE 3 JULY 1996 DATE JULY 12, 1996
-------------------------- --------------------------
FEDERAL ID # 56-1323952
<PAGE>
The information below marked by * and [ ] has been omitted pursuant to a request
for confidential treatment. The omitted portion has been separately filed with
the Commission.
ATTACHMENT NO. 1
SCOPE OF WORK
PROTOCOL NO. [_________] *
TABLE OF CONTENTS
SECTION PAGE
I. SERVICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Service Checklist
II. OVERALL PROJECT MANAGEMENT . . . . . . . . . . . . . . . . . . . . . 6
Overall Program and Study Strategy
Weekly Progress Reports
Project Team Meetings
Quality Assurance
III. STUDY DOCUMENT DEVELOPMENT . . . . . . . . . . . . . . . . . . . . . 8
Protocol Development
Informed Consent Form
Case Report Form
Study Reference Manual
IV. PROJECT INITIATION . . . . . . . . . . . . . . . . . . . . . . . . . 9
Investigational site Recruitment and Qualification
Regulatory Documents
Study Coordinator Training Meetings
Central Laboratory Services
Study Drug Management
Investigator Site Agreements
V. MANAGEMENT OF THE CLINICAL TRIAL . . . . . . . . . . . . . . . . . .12
Initiation Visits
Interim Monitoring Visits
Study Close-out Visits
Clinical Monitoring Communication
Communications with Sites
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<PAGE>
The information below marked by * and [ ] has been omitted pursuant to a request
for confidential treatment. The omitted portion has been separately filed with
the Commission.
SECTION PAGE
VI. MEDICAL MONITORING . . . . . . . . . . . . . . . . . . . . . . . . .15
Medical Support
Serious Adverse Event (SAE) and Expeditable AE Reporting
Expeditable AE Workflow
FDA Reporting
Drug Safety Databases
Drug Safety Procedures
VII. CLINICAL DATA MANAGEMENT . . . . . . . . . . . . . . . . . . . . . .17
Data Flow
Data Review Procedures
Programming
Data Entry/Optical Mark Recognition
Data Clarification with the Investigative Site
Quality Assurance
Adverse Event/Concomitant Medication Coding
Database Audit
VIII. BIOSTATISTICAL ANALYSIS. . . . . . . . . . . . . . . . . . . . . . .19
Statistical Analysis Plan
Final Analysis
Final Study Report
EXHIBIT NO. 1 - Quintiles Laboratories Limited, Proposal For Central Laboratory
Services
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<PAGE>
The information below marked by * and [ ] has been omitted pursuant to a request
for confidential treatment. The omitted portion has been separately filed with
the Commission.
Quintiles agrees to provide to Interneuron Project Management, Clinical,
Medical, Data Management, Statistical, Quality Assurance, and Central Laboratory
Services for the Citicoline trial to be conducted under Protocol No.
[_______________________________] *
Assumptions are based on the information provided to Quintiles in the
Interneuron Protocol No. [________________________] Interneuron's letter dated
May 7, 1996; and the *
Interneuron-Quintiles meeting in Cambridge, MA, on May 24, 1996.
I. SERVICES
--------------------------------------------------
STUDY SITES [______________________
______________________]
--------------------------------------------------
PATIENTS [_____________________]
[_____________________]
--------------------------------------------------
CRF PAGES
[_______________ [__]
________________ [__]
________________] [__]
--------------------------------------------------
TIME LINE
[_____________ [________]
______________ [________]
______________ [________]
______________ [________]
______________ [________]
______________ [________]
_____________] [________]
--------------------------------------------------
STUDY DURATION [________]
--------------------------------------------------
VISITS
[________] [________]
[________] [________]
[________] [________]
--------------------------------------------------
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<PAGE>
The information below marked by * and [ ] has been omitted pursuant to a request
for confidential treatment. The omitted portion has been separately filed with
the Commission.
--------------------------------------------------
INTERIM MONITORING [______________________
FREQUENCY _______________________
Frequency _______________________
______________________]
Source Document Review [________]
--------------------------------------------------
ESTIMATED NUMBER OF SAES [________]
--------------------------------------------------
STATISTICAL ANALYSIS
[________________ [________]
_________________ [________]
_________________ [________]
_________________] [________]
--------------------------------------------------
SERVICE CHECKLIST
- --------------------------------------------------------------------------------
- --------------------------------------------------------------------------------
ACTIVITY INTERNEURON QUINTILES
- --------------------------------------------------------------------------------
PROJECT MANAGEMENT X
STUDY START-UP
[_____________________________] X
[_____________________________] X
[_____________________________] X
[_____________________________] X
[_____________________________] X
[_____________________________] X
[_____________________________] X X
[_____________________________] X
[_____________________________] X
[_____________________________] X
[_____________________________] X
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<PAGE>
The information below marked by * and [ ] has been omitted pursuant to a request
for confidential treatment. The omitted portion has been separately filed with
the Commission.
- --------------------------------------------------------------------------------
ACTIVITY INTERNEURON QUINTILES
- --------------------------------------------------------------------------------
[_____________________________] X
[_____________________________] X
[_____________________________] X
[_____________________________] X
[_____________________________] X
[_____________________________] X
[_____________________________] X
[_____________________________] X
[_____________________________] X
[_____________________________] X X
[_____________________________] X
GCP AUDITS X
CLINICAL MONITORING
[_____________________________] X
[_____________________________] X
[_____________________________] X
[_____________________________] X
[_____________________________] X
[_____________________________] X
MEDICAL MANAGEMENT
[_____________________________] X
[_____________________________] X
[_____________________________] X
[_____________________________] X
DATA MANAGEMENT
[_____________________________] X
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<PAGE>
The information below marked by * and [ ] has been omitted pursuant to a request
for confidential treatment. The omitted portion has been separately filed with
the Commission.
- --------------------------------------------------------------------------------
ACTIVITY INTERNEURON QUINTILES
- --------------------------------------------------------------------------------
[_____________________________] X
[_____________________________] X
[_____________________________] X
[_____________________________] X
[_____________________________] X
[_____________________________] X
BIOSTATISTICS
[_____________________________] X
[_____________________________] X
[_____________________________] X
[_____________________________] X
OTHER ACTIVITIES
[_____________________________] X X
- --------------------------------------------------------------------------------
- --------------------------------------------------------------------------------
- --------------------------------------------------------------------------------
- --------------------------------------------------------------------------------
- --------------------------------------------------------------------------------
- --------------------------------------------------------------------------------
- --------------------------------------------------------------------------------
- --------------------------------------------------------------------------------
- --------------------------------------------------------------------------------
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<PAGE>
The information below marked by * and [ ] has been omitted pursuant to a request
for confidential treatment. The omitted portion has been separately filed with
the Commission.
II. OVERALL PROJECT MANAGEMENT
OVERALL PROGRAM AND STUDY STRATEGY
Quintiles has assigned a Project Manager to oversee this study. This individual
will be Interneuron's advocate within Quintiles, taking primary responsibility
for communications with Interneuron; providing day-to-day direction to the
Quintiles' project team; and communicating progress, issues, and problems with
proposed resolutions to Interneuron as needed. The Project Manager will
communicate the project goals, deadlines, and strategy to team members on a
timely basis ensuring that any questions will be addressed by the appropriate
resource within Quintiles. Changes to the scope of work, issues surrounding
scheduled activities, and other significant activities that affect the
administration of the contract will be monitored by the Project Manager.
The Project Manager will direct this project each step of the way, ensuring
adherence to schedules and to the project's scientific requirements. The
Project Manager will coordinate skilled technical Project Team members as
dictated by the scope of the project.
WEEKLY PROGRESS REPORTS
On a weekly basis, Quintiles will provide Interneuron with a study progress
report. The Quintiles' Administrative Management System (QAMS-TM-) will be
utilized to record study status information. QAMS-TM- will be programmed to
include the following information:
[_____________________________
_____________________________
_____________________________
_____________________________
_____________________________
_____________________________]
Custom features or special reports may be requested by Interneuron, but are not
included as part of the costs for this scope of work. Required reports will be
identified at the start of the study so that the system design is operational
prior to site initiation.
PROJECT TEAM MEETINGS
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The information below marked by * and [ ] has been omitted pursuant to a request
for confidential treatment. The omitted portion has been separately filed with
the Commission.
Key Quintiles Project Team members attended a joint Interneuron-Quintiles
face-to-face interdisciplinary team meeting at Quintiles' offices in Cambridge,
Massachusetts, on May 24, 1996, to address various issues related to the
project. The purpose of this meeting was to discuss primary points of contact
within each Company, reiterate project reporting requirements, review the
project schedule, and clarify other ad hoc issues.
Quintiles' CRAs assigned to this project will be available to meet with
Interneuron via teleconference prior to study initiation to discuss the project
in detail. The Quintiles' Project Team will hold internal team meetings on a
weekly basis (more or less frequently as project status dictates) to review the
progress of the project.
In addition to these internal team meetings, Quintiles' Project Manager will
participate in Project Team meetings with Interneuron throughout the course of
the project. These meetings will ensure the communication necessary to meet
study goals and successful completion of the project. Key members of Quintiles'
Project Team will attend these meetings. Quintiles assumes that these meetings
will occur primarily as teleconferences between Interneuron and Quintiles.
Occasional video teleconferences or face-to-face Project Team Meetings may also
occur either at Interneuron's or at Quintiles' offices.
[_______________________________________________________________________________
________________________________________________________________________________
____________]
At Interneuron's request, Quintiles' Clinical Monitoring Team assigned to this
project attended a training meeting presented in conjunction with the National
Stroke Association's conference in Colorado Springs, CO, on June 5, 1996.
[_______________________________________________________________________________
________________________________________________________________________________
___________________________________]
QUALITY ASSURANCE
The QA team will oversee all quality assurance activities, particularly with
regard to compliance to regulatory guidelines and company policies and
procedures, and to ensure that the formal quality control process is working as
intended within each business unit.
GCP AUDITS
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<PAGE>
The information below marked by * and [ ] has been omitted pursuant to a request
for confidential treatment. The omitted portion has been separately filed with
the Commission.
[_______________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
______________]
[_______________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
______________]
[_______________________________________________________________________________
________________________________________________________]
III. STUDY DOCUMENT DEVELOPMENT
PROTOCOL DEVELOPMENT
Interneuron will be responsible for preparing and providing to Quintiles a
final, approved protocol for this study. Quintiles anticipates the study
protocol will be in final form, requiring no revisions.
INFORMED CONSENT FORM
Interneuron will develop a model document with standard informed consent
language that will be mandatory for every site. Interneuron will be responsible
for all regulatory review and customization of the forms to meet local
regulations.
CASE REPORT FORM PREPARATION
Quintiles will develop Optical Mark Recognition (OMR) CRFs for this project.
Representatives from Quintiles' Clinical, Biostatistical, Medical, and Clinical
Data Management Departments will collaborate with Interneuron to determine the
CRF design that will provide efficient and complete collection of the necessary
data for the
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The information below marked by * and [ ] has been omitted pursuant to a request
for confidential treatment. The omitted portion has been separately filed with
the Commission.
study. Quintiles will design the CRFs according to Interneuron's
specifications. Quintiles has assumed that two (2) draft sets of the CRFs will
be provided to Interneuron for review and comment. Quintiles will incorporate
Interneuron's comments and generate a master set of CRFs, which will be
submitted to Interneuron for final review and approval. [_______________________
________________________________________________________________________________
________________]
STUDY REFERENCE MANUAL
Quintiles will develop a Study Reference Manual for use as a training and
reference tool by the Investigators. This manual will provide detailed
instructions on [_______________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
____] Sections of the manual will
include:[_______________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
__________________________] The manual will also serve as a consistent training
guide for each site as new site personnel are added during the conduct of the
study. As necessary, manuals will be kept current with updated sections
regarding any modifications to on-site study conduct.
IV. PROJECT INITIATION
INVESTIGATIONAL SITE RECRUITMENT AND QUALIFICATION
Quintiles will collaborate with Interneuron to identify [__________]
investigational sites to be qualified for consideration in this study.
Interneuron will provide Quintiles with the names, addresses, and telephone
numbers of the proposed Investigators for this study.
Quintiles will screen potential Investigators by telephone in order to ascertain
the Investigator's interest and ability to conduct this clinical trial. Once
interest and ability have been established, and a Confidential Disclosure
Agreement has been executed, the protocol and supporting documents will be
forwarded to the Investigator for review. Each site will be evaluated by a
member of Quintiles' monitoring staff through another telephone contact. During
this call the protocol will be discussed in depth along with other issues
necessary to determine a site's ability to participate in
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The information below marked by * and [ ] has been omitted pursuant to a request
for confidential treatment. The omitted portion has been separately filed with
the Commission.
the study,
[_______________________________________________________________________________
________________________________________________________________________________
______] Final site qualification will be confirmed in conjunction with the
site's initiation visit Quintiles anticipates that many of the sites recommended
by Interneuron for participation in this study will be sites with whom
[_______________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
________________________]
Interneuron will maintain the final approval of Investigator(s) selected by
Quintiles.
REGULATORY DOCUMENTS
Quintiles will be responsible for collecting from each site the regulatory
documents required for the study. Quintiles will obtain the clinical trial
documentation required by 21 CFR Section 312.53(c)(1),(2),(3). Quintiles will
transmit any other trial materials requested by Interneuron to each
Investigator. Quintiles' Regulatory Services staff will review all Investigator
documentation, including all informed consent forms, prior to submission to
Interneuron. When the Investigator is required to utilize a local IRB,
Quintiles will assist, as necessary, to coordinate the approval process.
[_______________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
_____________________________]
-12-
<PAGE>
The information below marked by * and [ ] has been omitted pursuant to a request
for confidential treatment. The omitted portion has been separately filed with
the Commission.
Quintiles will forward all required documentation to Interneuron for submission
to the FDA or other regulatory agency.
STUDY COORDINATOR TRAINING MEETINGS
Quintiles will plan, manage, and conduct meetings to provide project-specific
training to study coordinators for this project. Quintiles' responsibilities
will include preparing meeting presentations on relevant topics in conjunction
with Interneuron. Major agenda points to be covered by Quintiles and
Interneuron staff for these meetings, as well as other items, will be developed
and distributed prior to each meeting.
[_______________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
_______________________]
CENTRAL LABORATORY SERVICES
Quintiles Laboratories, Ltd. (QLAB) will be utilized for all centralized
clinical laboratory analyses and will interact with Quintiles with regard to
laboratory data transfers and patient laboratory accountability issues.
[_______________________________________________________________________________
________________________________________________________________________________
_____________________________________________]
QLAB will provide laboratory reports both electronically and in hard copy on a
routine basis.
[_______________________________________________________________________________
________________________________________________________________________________
_____________________________________________]
STUDY DRUG MANAGEMENT
[_______________________________________________________________________________
________________________________________________________________________________
_____________________________________________]
Quintiles will be responsible for drug accountability at the study sites, return
of unused drug to Interneuron, and drug supply reconciliation.
-13-
<PAGE>
The information below marked by * and [ ] has been omitted pursuant to a request
for confidential treatment. The omitted portion has been separately filed with
the Commission.
INVESTIGATOR SITE AGREEMENTS
Quintiles will negotiate and sign a Clinical Study Agreement with each of the
[___________] Principal Investigators/investigational sites for participation in
the study. The Agreements will include a grant and payment schedule using
guidelines provided by Interneuron. The form of this Agreement will be approved
in advance by Interneuron and any significant deviation from the approved,
standard contract will require Interneuron's written approval.
[____________________________________________
________________________________________________________________________________
___________]
Quintiles will assist Interneuron in formulating an equitable Investigator grant
and standard payment scheduled. Quintiles' estimated costs for this activity
assumes one standard payment schedule for all Investigators participating in the
study. Should Interneuron wish to offer greater flexibility to Investigators,
costs for payment administration will increase as payment schedule exceptions
are made.
Quintiles will track patient enrollment, discontinuation, and completion.
Periodically, a listing will be produced that describes the amounts due and
authorized to each Investigator according to the signed Clinical Study
Agreements. This listing will be accessed by Quintiles' Finance Department who
will prepare checks for each Principal Investigator/investigational site. These
checks will be signed, recorded, and distributed to the Principal
Investigator/investigational site. A record of disbursement will be provided to
Interneuron on a regular basis.
V. MANAGEMENT OF THE CLINICAL TRIAL
Quintiles monitors qualified by experience and training will perform the
monitoring responsibilities for this study.
Quintiles will assign a Lead CRA who will work with a Senior Clinical Project
Advisor to develop and coordinate the monitoring plan for this study. The
Project Advisor will have an ongoing role in clinical operations for the
project, participating in internal clinical group meetings and supporting the
Lead CRA in the management of clinical operation activities. The Lead CRA will
be responsible for coordinating the clinical monitoring team and will have
direct reporting responsibilities to the Project Manager.
[_______________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
_________]
-14-
<PAGE>
The information below marked by * and [ ] has been omitted pursuant to a
request for confidential treatment. The omitted portion has been separately
filed with the Commission.
INITIATION VISITS
Quintiles' monitors will perform a comprehensive site initiation visit to each
of the investigational sites. The Quintiles' monitor will meet with the site
Investigator and study site personnel to assure compliance with protocol
procedures and CRF completion. Drug shipment will be coordinated with the
initiation visit, and verification of drug inventory and dispensing procedures
will be reviewed. A complete review of the site's regulatory file will be
performed. This visit will confirm that the site is qualified to participate in
the study and ensure that regulations and documentation for the project are
understood and that all forms are completed correctly by the Investigator and
study site coordinator.
INTERIM MONITORING VISITS
[_______________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
_________]
[_______________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
_________]
[_______________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
_________]
Data queries generated as a result of data entry and review requiring on-site
resolution will be grouped by site and forwarded to the responsible monitor for
resolution at the next scheduled visit.
Quintiles' budget assumes that all study supplies (including study drug) will
reside at the investigational site and all monitoring for each site will take
place at one location. The need to monitor any additional locations will be
determined on a site-by-site basis
[_______________________________________________________________________________
_______________________________________________________________________________]
-15-
<PAGE>
The information below marked by * and [ ] has been omitted pursuant to a request
for confidential treatment. The omitted portion has been separately filed with
the Commission.
STUDY CLOSE-OUT VISITS
Quintiles will perform a study closeout visit to each of the sites participating
in this project.
[_______________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
_____________]
CLINICAL MONITORING COMMUNICATION
Quintiles will conduct [_______] monitoring calls between all CRAs assigned to
the project to discuss study issues and share information. This forum provides
an opportunity for the Lead CRA to coordinate monitoring efforts for maximum
efficiency across all regions/offices and to communicate important study updates
to the Project Team.
COMMUNICATIONS WITH SITES
Quintiles will contact the sites [________________] for patient enrollment
updates and to communicate any study administration information. All telephone
contacts with the sites will be documented. Quintiles' Clinical Monitoring Team
will be available by telephone to answer site questions throughout the course of
the study. After-hours coverage will be maintained by voicemail, and for urgent
matters, Quintiles will be accessible to sites through a 24-hour answering
service.
VI. MEDICAL MONITORING
MEDICAL SUPPORT
Quintiles will assign physician coverage to provide medical support for the
clinical monitors and Drug Safety Unit (as described in detail below). The
Project Medical Officer (PMO) will have a designated medical back-up and
Quintiles' medical staff will provide after hours on-call support for
Investigators to discuss project-related issues and questions.
[_______________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
_________]
-16-
<PAGE>
The information below marked by * and [ ] has been omitted pursuant to a request
for confidential treatment. The omitted portion has been separately filed with
the Commission.
SERIOUS ADVERSE EVENT (SAE) AND EXPEDITABLE AE REPORTING
[_______________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
_________]
[_______________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
_________]
EXPEDITABLE AE WORKFLOW
All expeditable AEs will be reported by investigative sites directly to
Quintiles' Drug Safety Unit using a dedicated toll-free AE hotline. Interneuron
will receive a standard report of information for each patient event (CRFs,
source documents, sponsor-specified safety reporting forms, and narratives).
Quintiles will provide to Interneuron a standard report that includes all
information available on each SAE case, typically within 24 hours of first
notification from the site.
FDA REPORTING
Any report classified by Quintiles as a possible FDA safety report will have a
report drafted that includes a description of the case and a discussion of the
case in light of similar reports (the latter information may be provided by
Interneuron). The case will be reviewed by Quintiles' Drug Safety senior
management Quintiles will confirm with Interneuron all IND safety reports to be
reported to the FDA. Quintiles will submit the safety report to Interneuron.
DRUG SAFETY DATABASES
Quintiles will create a real-time safety database that originates from the
expeditable safety reports. Quintiles does not expect that end-of-study
reconciliation of safety and clinical data will be necessary. In the event that
safety and clinical data require reconciliation, Quintiles will agree with
Interneuron on a set of key fields that will be reconciled on a periodic basis.
-17-
<PAGE>
The information below marked by * and [ ] has been omitted pursuant to a request
for confidential treatment. The omitted portion has been separately filed with
the Commission.
DRUG SAFETY PROCEDURES
Quintiles, in collaboration with Interneuron, will define the procedures for the
collection, evaluation, and reporting of SAEs. These procedures will include
definitions of expeditable events, delineation of SAE workflow from site to
Quintiles to Interneuron, and audits of the SAE system to guarantee proper
collection and reporting. Quintiles will be responsible for follow-up of SAE
reports and final preparation of the patient adverse event narratives. Based on
the specifications provided by Interneuron, Quintiles anticipates approximately
[_________________________________________________________]
VII. CLINICAL DATA MANAGEMENT
[_______________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
__________________________________]
DATA FLOW
Data will be collected from the study site by a citicoline project study
monitor. Only completed CRFs will be collected.
Once data are received at Quintiles, they will immediately go through a
preliminary auditing procedure and Clinical Document Administration, which
includes date stamping, log in, and transmittal verification.
Documents will be tracked on a patient-by-patient, page-by-page basis. Tracking
reports will be generated on a regular basis to identify and account for missing
pages, missing visits, and overall data accumulation. In addition, verification
of transmittals will occur on a regular basis with appropriate feedback to the
citicoline study team.
DATA REVIEW PROCEDURES
Clinical data will be reviewed using specifications developed by Quintiles and
approved by Interneuron. A combination of three types of data review procedures
will be employed:
[_______________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
_________________________________]
-18-
<PAGE>
The information below marked by * and [ ] has been omitted pursuant to a request
for confidential treatment. The omitted portion has been separately filed with
the Commission.
PROGRAMMING
Quintiles will develop and test a: data entry system including data entry
screens and programmed error checks in SAS/FSP.
DATA ENTRY/OPTICAL MARK RECOGNITION
[_______________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
_______________________________________________________________________________]
[_______________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
_______________________________________________]
[_______________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
__________________________________]
[_______________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
__________________________________]
DATA CLARIFICATION WITH THE INVESTIGATIVE SITE
Discrepancies or problems identified either during data review or entry will be
referred by the Quintiles data processing staff to the citicoline project study
monitor for resolution. All clarifications will be documented in writing using
Quintiles' standard operating procedures. This system represents a "controlled"
system in the sense that a full audit trail is produced and maintained for
problems encountered during both the
-19-
<PAGE>
The information below marked by * and [ ] has been omitted pursuant to a request
for confidential treatment. The omitted portion has been separately filed with
the Commission.
data monitoring and data entry processes and for the resolution of each problem
referred to the study monitor.
QUALITY ASSURANCE
The quality of the final database is assured through a series of quality control
steps applied during processing, including double entry (or double scanning) of
all data. In addition, a final quality control audit will be performed prior to
locking the database. This is accomplished through proofreading a statistically
determined sample of data forms based on a number of criteria. The audit will
involve a 100% check of critical . variables identified by Interneuron and
Quintiles, and a 10% check of all other variables. The audit is conducted by
comparing the data forms against the final database. All audit results will be
documented for review by Interneuron.
ADVERSE EVENT/CONCOMITANT MEDICATION CODING
Quintiles will perform encoding of adverse events using
[____________________________] provided by Interneuron. Similarly, Quintiles
will provide encoding of prior or concurrent medications using
[______________________________]
DATABASE AUDIT
[_______________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
_________________________________]
VIII. BIOSTATISTICAL ANALYSIS
[_______________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
_________________________________]
STATISTICAL ANALYSIS PLAN
-20-
<PAGE>
The information below marked by * and [ ] has been omitted pursuant to a request
for confidential treatment. The omitted portion has been separately filed with
the Commission.
Quintiles' Biostatisticians will prepare a data analysis plan that outlines the
trial's key efficacy and safety objectives, specifies the way in which variables
will be analyzed, and describes ancillary information that will be summarized in
the final report.
The analysis plan will summarize both descriptive and analytic statistics so
that the resulting reports will include a balance of understandable summaries of
the data, as well as the appropriate statistical tests.: All analysis plans will
be reviewed by a Senior Biostatistician at Quintiles before they are sent to
Interneuron. After approval of these plans by Interneuron, Quintiles'
Biostatisticians will finalize the analysis plan that will become the blueprint
for programming, analysis, and report-writing.
The Statistical Programmers assigned to this project will develop SAS programs,
and run the table output and patient listings required under the analysis plans.
Clinical Research Scientists will work with the Biostatistician during the
review of the analysis plans to prepare for clinical summary integration into
the final study reports Biostatistical Assistants will perform data quality
control activities reviewing all data listings, tables, and reports according to
Quintiles' RDQC standard SOPs.
[_______________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
________________________________________________________________]
FINAL ANALYSIS
Quintiles will prepare [______________] drafts of the final analysis for review
and comment by Interneuron. Once final comments from Interneuron are received,
the final analysis can be generated. The final analysis will be generated based
on the final, approved statistical analysis plan.
FINAL STUDY REPORT
Quintiles will prepare the integrated statistical clinical report section. The
draft final study report will be reviewed by internal Quintiles senior staff who
have the appropriate statistical and medical expertise.
Once internally reviewed, Quintiles will provide Interneuron with the draft
final study report for review and comment. The time for Interneuron's review is
estimated to be
-21-
<PAGE>
The information below marked by * and [ ] has been omitted pursuant to a request
for confidential treatment. The omitted portion has been separately filed with
the Commission.
two (2) weeks. The report will be revised as needed based on comments from
Interneuron's review. Quintiles will deliver the final study report after
incorporating Interneuron's comments on the draft. Electronic copies of the
final study reports will be included. For scheduling purposes for this proposal,
Quintiles estimates that the final study report will be submitted for review two
months after database lock.
-22-
<PAGE>
The information below marked by * and [ ] has been omitted pursuant to a request
for confidential treatment. The omitted portion has been separately filed with
the Commission.
EXHIBIT NO. 1
QUINTILES LABORATORIES LIMITED
PROPOSAL FOR CENTRAL LABORATORY SERVICES
INTERNEURON PHARMACEUTICALS, INC.
PROTOCOL [_________] *
JULY 3, 1996
REVISED FROM APRIL 11, 1996
1
<PAGE>
The information below marked by * and [ ] has been omitted pursuant to a request
for confidential treatment. The omitted portion has been separately filed with
the Commission.
OVERVIEW
Quintiles Laboratories Limited (QLAB) is a global centralized clinical trial
laboratory serving exclusively clients in the pharmaceutical and biotechnology
marketplace. Operating as an independent business unit in the Quintiles family,
QLAB conducts clinical trials in conjunction with Quintiles' Contract Research
Organization (CRO) divisions, with other CROs or directly with sponsor
pharmaceutical companies. Quintiles Laboratories also provides centralized
clinical trial activities for European based studies from our facility in
Edinburgh, Scotland. Using identical instrumentation, reference ranges and
clinical trial software, QLAB North America and QLAB Europe provide the most
comprehensive North American and European central laboratory capabilities
currently in existence.
APPROACH TO AND EXPERIENCE IN NORTH AMERICAN AND EUROPEAN PROJECTS
Centralized clinical laboratory services for the U.S. and Canadian sites are
provided by Quintiles Laboratories in Atlanta, GA. European investigator sites
are serviced by Quintiles Laboratories Europe out of Edinburgh, Scotland.
[_______________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
_________________________________]
2
<PAGE>
The information below marked by * and [ ] has been omitted pursuant to a request
for confidential treatment. The omitted portion has been separately filed with
the Commission.
[_______________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
_________________________________]
FACILITIES
[_______________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
_________________________________]
Both the North American and the European facilities are continuously monitored
by security specialists to ensure maximal protection against unauthorized access
to proprietary clinical trial materials and to provide early detection in the
event that the temperature controlled environments should go out of range or an
equipment failure should occur.
LICENSURE AND PROFICIENCY
[_______________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
_________________________________]
3
<PAGE>
The information below marked by * and [ ] has been omitted pursuant to a request
for confidential treatment. The omitted portion has been separately filed with
the Commission.
ANALYTICAL CAPABILITIES
Both QLAB North America and QLAB Europe are comprehensive, full-service
facilities which provide analytical testing and data management services to meet
the needs of Phase I through Phase IV clinical trial programs. Both laboratories
use state of the art, automated instrumentation, chosen to optimize accuracy and
precision. High volume instrumentation are equipped with bar code readers and
are interfaced with the respective North American and European mainframe
databases.
[_______________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
_________________________________]
ANALYTICAL CHEMISTRY AND METHODS DEVELOPMENT
[_______________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
_________________________________]
PROTOCOL PLANNING AND MANAGEMENT
QLAB's staff of experienced clinical trial professionals will work with
Interneuron's project team or their designate in the planning of the laboratory
aspects of the
4
<PAGE>
The information below marked by * and [ ] has been omitted pursuant to a
request for confidential treatment. The omitted portion has been separately
filed with the Commission.
protocols. A customized database which defines protocol specific parameters will
be developed at the beginning of the process. This approach will ensure that all
aspects of the program will be implemented smoothly and that the worldwide
laboratory database fully reflects the requirements of the protocol.
At study initiation, the design and development of customized visit and site
specific laboratory collection materials, laboratory reporting forms and
standard operating procedures will occur. Once Interneuron's approval of the
laboratory-related study materials has been received, a full presentation of the
laboratory aspects of the program can occur at the Investigator Meetings.
Throughout the program, professional, efficient and timely response to both
investigator's sites and Interneuron will be a priority.
Routine reporting of study status is available to assist Interneuron in the
study management of enrollment levels on a site by site basis. Additionally,
Interneuron may request patient abnormality or alert flag summaries to assist in
the identification of potentially early trends in the clinical trail.
Throughout the program, or at study conclusion, a complete audited database will
be electronically transmitted to Interneuron in a format and media that is
specified at the inception of the trial. This approach ensures that data is
ready for analysis as it is available from the central laboratories.
5
<PAGE>
The information below marked by * and [ ] has been omitted pursuant to a
request for confidential treatment. The omitted portion has been separately
filed with the Commission.
[_______________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
_________________________________]
SPECIMEN COLLECTION AND RECEIPT
The designated QLAB facility will work with Interneuron to provide visit-
specific collection materials and overnight express courier shipping which will
meet the needs of Interneuron's protocol in the most cost-effective manner.
Because QLAB recognizes that the results for all specimens are important for the
successful and timely completion of your study, QLAB will provide:
[_______________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
_________________________________]
SAMPLE MANAGEMENT AND ARCHIVAL SERVICES
QLAB can provide sophisticated specimen management services which allows
deferred shipment of Interneuron's specimens to the central laboratory.
Collection of samples intended for periodic shipment to QLAB by the
investigators throughout Europe and North America are facilitated by use of pre-
addressed foam mailers.
6
<PAGE>
The information below marked by * and [ ] has been omitted pursuant to a request
for confidential treatment. The omitted portion has been separately filed with
the Commission.
Additionally, specimens are held at both facilities for seven days to allow for
repeat testing when needed.
LABORATORY REPORTING
Laboratory Reports can be designed as a Case Report Form page and thereby allow
the investigator to indicate the level of clinical significance, etiology coding
and medical comments if desired. To assist the investigator in patient
management, critical test results on the laboratory report can be flagged by
protocol-specific telephone and panic alerts as designated by Interneuron. Delta
flagging can also be used on the laboratory report to alert the investigator of
early changes in a particular result relative to a patient's baseline result.
Exclusion flagging is provided so assist the investigator in the enrollment
phase of the trial, or to identify prospective patients for study withdrawal.
[_______________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
_________________________________]
QLAB laboratory information system (QLIMS) provides the following laboratory
reporting features to support your clinical trial:
7
<PAGE>
The information below marked by * and [ ] has been omitted pursuant to a
request for confidential treatment. The omitted portion has been separately
filed with the Commission.
[_______________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
_________________________________]
[_______________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
_________________________________]
STUDY DESIGN AND ANALYTICAL SERVICES
[_______________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
_________________________________________________________________]
I. ROUTINE SAFETY MEASURES
8
<PAGE>
The information below marked by * and [ ] has been omitted pursuant to a request
for confidential treatment. The omitted portion has been separately filed with
the Commission.
[__________________________________________________________________________
___________________________________________________________________________
___________________________________________________________________________
________________________________________________]
[__________________________________________________________________________
___________________________________________________________________________
___________________________________________________________________________
___________________________________________________________________________
________________________________________________]
[__________________________________________________________________________
___________________________________________________________________________
___________________________________________________________________________
________________________________________________]
[__________________________________________________________________________
___________________________________________________________________________
___________________________________________________________________________
9
<PAGE>
The information below marked by * and [ ] has been omitted pursuant to a request
for confidential treatment. The omitted portion has been separately filed with
the Commission.
___________________________________________________________________________
__________________]
[__________________________________________________________________________
___________________________________________________________________________
___________________________________________________________________________
________________________________________________]
[__________________________________________________________________________
___________________________________________________________________________
___________________________________________________________________________
________________________________________________]
[__________________________________________________________________________
__________________]
[__________________________________________________________________________
___________________________________________________________________________
___________________________________________________________________________
________________________________________________]
10
<PAGE>
The information below marked by * and [ ] has been omitted pursuant to a
request for confidential treatment. The omitted portion has been separately
filed with the Commission.
ANALYTICAL STANDARDS AND CERTIFICATION
[_______________________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
_________________________________]
ANALYTICAL METHODOLOGY COMPARABILITY
[____________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
____________________________________________]
SPECIMEN STABILITY
[____________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
____________________________________________]
TEST PRIORITY IN THE EVENT OF INSUFFICIENT SPECIMENS
[____________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
____________________________________________]
TEST REPORTING UNITS
[____________________________________________________________________
________________________________________________________________________________
________________________________________________________________________________
____________________________________________]
11
<PAGE>
The information below marked by * and [ ] has been omitted pursuant to a request
for confidential treatment. The omitted portion has been separately filed with
the Commission.
LABORATORY EVENTS SCHEDULE
INTERNEURON PHARMACEUTICALS, INC.
PHASE III, ISCHEMIC STROKE STUDY
PROTOCOL [_________]
SITES: [_________]
ENROLLMENT PERIOD: [_________]
TREATMENT PERIOD: [_________]
FOLLOW UP PERIOD: [_________]
START DATE: [_________]
<TABLE>
<CAPTION>
- -------------------------------------------------------------------------------------------
TREATMENT PHASE/
WEEKS [1-6]
BASELINE/ -------------------- EARLY UNSCHED/
ASSESSMENTS PERFORMED DAY 0 [HOSPITAL TERM RETEST
DISCHARGE] WEEK[6]
- -------------------------------------------------------------------------------------------
<S> <C> <C> <C> <C> <C>
- -------------------------------------------------------------------------------------------
No. of Patients [___] [___] [___] [_________] [________]
- -------------------------------------------------------------------------------------------
Chemistry w/18 Constituents [_] [_] [_] [_] [_]
- -------------------------------------------------------------------------------------------
Lipid Profile [_] [_] [_] [_] [_]
- -------------------------------------------------------------------------------------------
Hematology w/Differential & [_] [_] [_] [_] [_]
Platelet Count
- -------------------------------------------------------------------------------------------
Coagulation Profile [_] [_] [_] [_] [_]
- -------------------------------------------------------------------------------------------
Urinalysis w/Microscopic [_] [_] [_] [_] [_]
- -------------------------------------------------------------------------------------------
Serum Pregnancy [_] [_] [_] [_] [_]
- -------------------------------------------------------------------------------------------
</TABLE>
KEY:
- - - SCHEDULED TEST
- - - UNSCHEDULED TEST
- - - REQUIRED FOR FEMALE PATIENTS OF CHILDBEARING POTENTIAL ONLY. OPTIONAL
FOR BUDGETING PURPOSES.
12
<PAGE>
The information below marked by * and [ ] has been omitted pursuant to a request
for confidential treatment. The omitted portion has been separately filed with
the Commission.
PROVISIONAL SERVICES BUDGET
INTERNEURON PHARMACEUTICALS, INC.
PHASE III, ISCHEMIC STROKE STUDY
PROTOCOL [____________]
<TABLE>
<CAPTION>
NO. OF PATIENT
SCHEDULED VISITS VISITS FEE EXTENDED FEE
<S> <C> <C> <C>
- ------------------------------------------------------------------------------------------
DATA BASE CONSTRUCTION & MAINTENANCE [_] [________] [____________]
- ------------------------------------------------------------------------------------------
BASELINE/DAY 0 VISIT [________________] VISIT & [_____] [______] [__________]
WEEK [_] VISIT
- ------------------------------------------------------------------------------------------
PROVISIONAL SERVICES BUDGET [___________]
- ------------------------------------------------------------------------------------------
UNSCHEDULED & ANCILLARY
SERVICES DESCRIPTION FEE FOR SERVICE
- ------------------------------------------------------------------------------------------
UNSCHEDULED VISIT FEE [___________________________________] [_________]
- ------------------------------------------------------------------------------------------
EARLY TERM VISIT FEE [___________________________________] [_________]
- ------------------------------------------------------------------------------------------
OPTIONAL TEST FEE [___________________________________] [_________]
- ------------------------------------------------------------------------------------------
ELECTRONIC DATA TRANSFER [___________________________________] [_________]
(MONTHLY)
- ------------------------------------------------------------------------------------------
WEEKLY STATUS REPORT [___________________________________] [_________]
- ------------------------------------------------------------------------------------------
</TABLE>
13
<PAGE>
The information below marked by * and [ ] has been omitted pursuant to a request
for confidential treatment. The omitted portion has been separately filed with
the Commission.
LABORATORY REQUIREMENTS
INTERNEURON PHARMACEUTICALS, INC.
PHASE III, ISCHEMIC STROKE STUDY
PROTOCOL [__________]
CHEMISTRY [_________]
[_________]
[_________] URINALYSIS
[_________] [_________]
[_________] [_________]
[_________] [_________]
[_________] [_________]
[_________] [_________]
[_________] [_________]
[_________] [_________]
[_________] [_________]
[_________]
[_________] ENDOCRINOLOGY
[_________] [_________]
[_________]
[_________] [_________]
[_________]
[_________]
[_________]
LIPID PROFILE
[_________]
[_________]
[_________]
[_________]
HEMATOLOGY
[_________]
[_________]
[_________]
[_________]
[_________]
[_________]
[_________]
[_________]
COAGULATION PROFILE *
[_________]
[_________]
14
<PAGE>
The information below marked by * and [ ] has been omitted pursuant to a request
for confidential treatment. The omitted portion has been separately filed with
the Commission.
ATTACHMENT NO.2
PAYMENT SCHEDULE
PROTOCOL NO. [________] *
PROJECT BUDGET
ACTIVITY BUDGET
Interneuron/Quintiles Study Start-up Meeting-May 24, 1996
[ ] Quintiles staff to attend [$ ]
Project Management and Support [ ]
Study Doc. Development/Project Initiation/Investigator Contracts [ ]
Pre-study Site Evaluation Visits [ ]
Study Coordinator Meeting Planning/Attendance/Participation [ ] [ ]
National Stroke Assn. Training Meeting [ ]
Clinical Trial Monitoring [ ]
Clinical Trial In-House/Site Contact/CRA Coordination/Support [ ]
Quality Assurance Audits [ ] [ ]
Medical Support: PMO Services, AE Processing and Reporting [ ]
Study Drug Management [ ]
Data Management (includes estimated OMR CRF design/development) [ ]
Biostatistical Analysis [ ]
Final Biostatistical Report and Final Integrated Clinical Study Report [ ]
Quintiles Laboratories Ltd. [ ]
TOTAL QUINTILES' FEES [$ ]
May 24, 1996 Meeting Travel [ ]
Estimated Monitoring Travel [ ]
Estimated QA Audit Travel [ ]
Estimated Study Coordinator Meeting [ ] [ ]
Nat'l Stroke Assn. Training Meeting Travel [ ]
Miscellaneous Costs: [ ]
Shipping costs (non-drug), telephone/fax, postage
copying/printing, supplies [ ]
TOTAL PASS-THROUGH COSTS [$ ]
<PAGE>
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for confidential treatment. The omitted portion has been separately filed with
the Commission.
MONITORING VISIT UNIT COSTS
MONITORING ESTIMATED
ACTIVITY TIME TRAVEL COSTS TOTAL
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Pre-Study Site Evaluation Visit [ ] [ ] [ ]
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Site Initiation Visit [ ] [ ] [ ]
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Interim Monitoring Visit [ ] [ ] [ ]
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Site Closeout Visit [ ] [ ] [ ]
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for confidential treatment. The omitted portion has been separately filed with
the Commission.
BUDGET NOTE
GENERAL
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PROJECT INITIATION
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-3-
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for confidential treatment. The omitted portion has been separately filed with
the Commission.
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CLINICAL MONITORING AND PROJECT MANAGEMENT
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DATA MANAGEMENT
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BIOSTATISTICAL ANALYSIS
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for confidential treatment. The omitted portion has been separately filed with
the Commission.
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The information below marked by * and [ ] has been omitted pursuant to a request
for confidential treatment. The omitted portion has been separately filed with
the Commission.
ATTACHMENT NO.3
PAYMENT SCHEDULE
PROTOCOL NO. [________] *
Interneuron Pharmaceutical, Inc. agrees to pay Quintiles for services rendered
upon receipt of invoice according to the payment schedule detailed below.
A. Quintiles Fees
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DATE
PAYMENT --------------------------
NO. AMOUNT INVOICED DUE
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#1 [$ ______] [_________________]
#2 [$ ______] [ ______] [ ______]
#3 [$ ______] [ ______] [ ______]
#4 [$ ______] [ ______] [ ______]
#5 [$ ______] [ ______] [ ______]
#6 [$ ______] [ ______] [ ______]
#7 [$ ______] [ ______] [ ______]
#8 [$ ______] [ ______] [ ______]
#9 [$ ______] [ ______] [ ______]
#10 [$ ______*] [ ______] [ ______]
B. Pass-Through Costs
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VARIABLE COST ITEMS
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