EXHIBIT 10.45

 

AMENDMENT #4

 

Protocol # V1T—02-08961X

 

PRA Project ID #1600

 

THIS AMENDMENT #4 (“Amendment #4”), dated as of the 18th day of August, 2003
(the “Effective Date”), by and between CroMedica Global, Inc. (“CroMedica”) and
ISTA Pharmaceuticals (formerly known as Advanced Corneal Systems, Inc.
(hereinafter “Sponsor”).

 

W I T N E S S E T H:

 

WHEREAS, under the terms of a certain Contract for Clinical Research Agreement
(the “Agreement”), dated the 8th day of September, 1998 as amended by Amendment
#1, dated October 11, 2000, Amendment #2, dated February 21, 2001, and Amendment
#3, dated December 5, 2001 by and between the parties, Sponsor agreed to retain
CroMedica, and CroMedica agreed to be retained by Sponsor, to perform the
Services as more particularly described in the Agreement pursuant to the terms
of the Agreement; and

 

WHEREAS, the parties hereto have entered into certain additional agreements with
respect to modification of the Agreement, and which they desire to memorialize
in this Amendment #4;

 

NOW, THEREFORE, in consideration of the premises and of the following mutual
promises, covenants and conditions hereinafter set forth, the parties hereto
agree as follows:

 

1. Change in Name of CroMedica. The parties acknowledge that CroMedica Global
Inc. is now doing business as Pharmaceutical Research Associates, Inc. (“PRA”),
and that this change of name does not alter the terms and conditions set forth
in the Agreement. All references to CroMedica in the Agreement shall now be
construed to mean references to PRA. The terms of the Agreement are only
modified to the extent of the amendments set forth below.

 

2. Payment and Performance Schedule. The Services to be provided by PRA pursuant
to the Agreement are hereby amended to reflect that Sponsor has assumed
responsibility for monitoring certain investigative sites, and to reflect PRA’s
monitoring visits and safety reporting through December 2002. These changes to
the Services are described in the revised Attachment 2, which is attached hereto
and incorporated herein by reference.

 

3. Ratification of Balance of Agreement. In all other respects, the terms of the
Agreement are hereby ratified and affirmed by each of the parties hereto.

 

4. Headings. The headings in this Amendment #4 are for convenience of reference
only and shall not affect its interpretation.

 

Page 1 of 15

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IN WITNESS WHEREOF, the parties hereto, each by a duly authorized
representative, have executed this Amendment #4 as of the date first written
above.

 

PHARMACEUTICAL RESEARCH

ASSOCIATES, INC.

      ISTA PHARMACEUTICALS

By:

 

/s/ Greg A. Johnson

      By:  

/s/ Risa L. Grillone

   

--------------------------------------------------------------------------------

         

--------------------------------------------------------------------------------

   

Greg A. Johnson

         

Authorized Signature

                 

Title: Vice President, Operations

     

Title: Vice President, Clinical Research

Date: 22 Aug 2003

     

Date: 16 Sept 03

 

Page 2 of 15

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REVISED ATTACHMENT 2

AMENDED PROJECT SPECIFICATIONS

 

     Unit Cost

--------------------------------------------------------------------------------

   Original
Study Total

--------------------------------------------------------------------------------

   Adjustment
Amendment
2

--------------------------------------------------------------------------------

   Revised
Study Total
($US)

--------------------------------------------------------------------------------

   Adjustment
Amendment
3 Occurring
to Nov.
2001

--------------------------------------------------------------------------------

   Adjustment
Amendment
3 Occurring
post Nov.
2001

--------------------------------------------------------------------------------

   Revised
Study Total
($US)

--------------------------------------------------------------------------------

   Adjustment
Amendment
4

--------------------------------------------------------------------------------

    Revised
Study Total
($US)

--------------------------------------------------------------------------------

              Amendment
2

--------------------------------------------------------------------------------

         Amendment
#3

--------------------------------------------------------------------------------

     Amendment
#4

--------------------------------------------------------------------------------

Up front (20%)

        563,525.00         563,525.00              563,525.00         
563,525.00 Australia Regulatory Submission    10,000.00    10,000.00        
10,000.00              10,000.00          10,000.00

CRF Finalization

   8,580.00    8,580.00         8,580.00              8,580.00          8,580.00

Site Recruitment:

                                             

Canadian

   200.00    2,400.00         2,400.00              2,400.00    (2,400.00 )  
0.00

U.S.

   240.00    2,880.00         2,880.00              2,880.00    (2,880.00 )  
0.00

Australia

   240.00    2,400.00         2,400.00              2,400.00    (2,400.00 )  
0.00

AMENDMENT #4 ADJUSTMENT: Revised based on actual number of site identifications
performed:

5 Canadian, 12 US, 8 Australian.

                                             

Canadian

   200.00                                  1,000.00     1,000.00

U.S.

   240.00                                  2,880.00     2,880.00

Australia

   240.00                                  1,920.00     1,920.00

Initiation Visits:

                                             

Canadian

   600.00    7,200.00         7,200.00              7,200.00    (7,200.00 )  
0.00

U.S.

   720.00    18,720.00         18,720.00              18,720.00    (18,720.00 )
  0.00

Australia

   1,080.00    10,800.00         10,800.00              10,800.00    (10,800.00
)   0.00 AMENDMENT #4 ADJUSTMENT: Revised based on actual number of initiations
performed: 9 Canadian, 31 US, 8 Australian.                                   
          

Canadian

   600.00                                  5,400.00     5,400.00

U.S.

   720.00                                  22,320.00     22,320.00

Australia

   1,080.00                                  8,640.00     8,640.00

 

Page 3 of 15

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     Unit Cost

--------------------------------------------------------------------------------

   Original
Study Total

--------------------------------------------------------------------------------

   Adjustment
Amendment
2

--------------------------------------------------------------------------------

   Revised
Study Total
($US)

--------------------------------------------------------------------------------

   Adjustment
Amendment
3 Occurring
to Nov.
2001

--------------------------------------------------------------------------------

   Adjustment
Amendment
3 Occurring
post Nov.
2001

--------------------------------------------------------------------------------

   Revised
Study Total
($US)

--------------------------------------------------------------------------------

   Adjustment
Amendment
4

--------------------------------------------------------------------------------

    Revised
Study Total
($US)

--------------------------------------------------------------------------------

              Amendment
2

--------------------------------------------------------------------------------

         Amendment
#3

--------------------------------------------------------------------------------

     Amendment
#4

--------------------------------------------------------------------------------

Interim Visits:

                                             

Canadian

   1,200.00    183,600.00                                    

U.S.

   1,440.00    1,156,680.00                                    

Australia

   1,280.00    124,800.00         124,800.00                          

AMENDMENT 2 ADD:

                                              7 additional monitoring visits per
site related to 3 interim analyses and resolution of clinical review queries not
originally contracted:                                              

Canadian

                                             

11 sites x 7 visits

             92,400.00    276,000.00                          

AMENDMENT #2

ADJUSTMENT: Per visit rate adjusted to $1800/visit for visits occurring
post-March, 2001 due to increased patient population, extensive CRF changes,
increased on site effort

                                             

  58 x $1,200 =     69,600

                                             

  38 x $1,800 =     68,400

                                             

134 x $1,800 =   241,200

                                             

Total                          $379,200

                       22,800.00    80,400.00    379,200.00    (379,200.00 )  
0.00

U.S.

                                             

58 sites x 7 visits

             584,640.00    1,741,320.00                          

AMENDMENT #2

ADJUSTMENT: Per visit rate adjusted to $2160/visit for visits occurring
post-March, 2001 due to increased patient population, extensive CRF changes,
increased on site effort

                                             

608 x $1,440 =     875,520

                                             

 

Page 4 of 15

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     Unit Cost

--------------------------------------------------------------------------------

  

Original

Study Total

--------------------------------------------------------------------------------

   Adjustment
Amendment
2

--------------------------------------------------------------------------------

   Revised
Study Total
($US)

--------------------------------------------------------------------------------

   Adjustment
Amendment
3 Occurring
to Nov.
2001

--------------------------------------------------------------------------------

   Adjustment
Amendment
3 Occurring
post Nov.
2001

--------------------------------------------------------------------------------

   Revised
Study Total
($US)

--------------------------------------------------------------------------------

   Adjustment
Amendment
4

--------------------------------------------------------------------------------

    Revised
Study Total
($US)

--------------------------------------------------------------------------------

              Amendment
2

--------------------------------------------------------------------------------

         Amendment
#3

--------------------------------------------------------------------------------

     Amendment
#4

--------------------------------------------------------------------------------

212 x $2,160 =      457,920

                                             

389 x $2,160 =      840,240

                                             

Total                          $2,173,680

                       152,640.00    279,720.00    2,173,680.00    (2,173,680.00
)   0.00

AMENDMENT 3 ADD:

                                              North America: 2.25 visits per
site to take total visits per site to 22 over life of study Australia: 5 visits
per site to take total visits per site to 16 over life of study               
                              

Canadian

                                             

11 sites x 2.25 visits

   1,800.00                        44,550.00    44,550.00    (44,550.00 )   0.00

U.S.

                                             

58 sites x 2.25 visits

   2,160.00                        281,880.00    281,880.00    (281,880.00 )  
0.00

Australia

                                             

9 sites x 5 visits

   1,280.00                        57,600.00    182,400.00    (182,400.00 )  
0.00

 

Page 5 of 15

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     Unit Cost

--------------------------------------------------------------------------------

   Original
Study Total

--------------------------------------------------------------------------------

   Adjustment
Amendment
2

--------------------------------------------------------------------------------

   Revised
Study Total
($US)

--------------------------------------------------------------------------------

   Adjustment
Amendment
3 Occurring
to Nov.
2001

--------------------------------------------------------------------------------

   Adjustment
Amendment
3 Occurring
post Nov.
2001

--------------------------------------------------------------------------------

   Revised
Study Total
($US)

--------------------------------------------------------------------------------

   Adjustment
Amendment
4

--------------------------------------------------------------------------------

   Revised
Study Total
($US)

--------------------------------------------------------------------------------

              Amendment
2

--------------------------------------------------------------------------------

         Amendment
#3

--------------------------------------------------------------------------------

      Amendment
#4

--------------------------------------------------------------------------------

AMENDMENT #4

ADJUSTMENT: North American interim per visit rate increased by 4 hours/visit for
visits occurring between Sept 11, 2001 and Nov 30, 2002 due to increased travel
time related to airport security measures.

 

Effective Dec 1, 2002 CRAs reallocated to reduce travel time to pre-Sept 11,
2001 allowance of 4 hours/visit, with ISTA assuming responsibility for visits to
sites requiring additional travel. PRA will monitor 9 Canadian sites, 8 US
sites, and 5 Australian sites to June 2003. Per visit rate increased to include
1.5 hours per visit as discussed with Lisa Grillone December 9, 2002, to reflect
additional in-house effort by CRAs for telephone query resolution in order to
accommodate less frequent visit schedule.

                                             Canada: 92 visits pre-Sept 11/01
(58 @ $1200, 34 @ $1800); 29 visits post-Sept 11/01 to Dec 31/02 @ $2100; 11 -
one day visits projected to Jun 30, 2003 @$1912/visit based on assumption that
CRA allocations can be revised to reduce travel time to four hours/visit.   
1,200.00
1,800.00
2,100.00

 

 

1,912.00

                                 69,600.00
61,200.00
60,900.00

 

 

21,032.00

   69,600.00
61,200.00
60,900.00

 

 

21,032.00

 

Page 6 of 15

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     Unit Cost

--------------------------------------------------------------------------------

   Original
Study Total

--------------------------------------------------------------------------------

   Adjustment
Amendment
2

--------------------------------------------------------------------------------

    Revised
Study Total
($US)

--------------------------------------------------------------------------------

   Adjustment
Amendment
3 Occurring
to Nov.
2001

--------------------------------------------------------------------------------

   Adjustment
Amendment
3 Occurring
post Nov.
2001

--------------------------------------------------------------------------------

   Revised
Study Total
($US)

--------------------------------------------------------------------------------

   Adjustment
Amendment
4

--------------------------------------------------------------------------------

   Revised
Study Total
($US)

--------------------------------------------------------------------------------

             Amendment
2

--------------------------------------------------------------------------------

         Amendment
#3

--------------------------------------------------------------------------------

      Amendment
#4

--------------------------------------------------------------------------------

Canada: 2 day visits from Jan 1, 2003 to June 30, 2003: 7 @ $2,625 per visit   
2,625.00                                   18,375.00    18,375.00

U.S. 754 visits pre-Sept

11/01 (608 @ $1440, 146 @ $2160); 207 visits post-Sept 11/01 to Dec 31/02 @
$2520; 11 - one day visits projected to June 30, 2003 @ $2300/visit based on
assumption that CRA allocations can be revised to reduce travel time to four
hours/visit.

   1,440.00
2,160.00
2,520.00

 

2,300.00

                                  875,520.00
315,360.00
521,640.00

 

25,300.00

   875,520.00
315,360.00
521,640.00

 

25,300.00

U.S.: 2 day visits from Jan 1, 2003 to June 30, 2003: 1 @ $3,150 per visit   
3,150.00                                   3,150.00    3,150.00 Australia: 62
visits to Sept 30/02 (not including unmasked monitoring visits); 8 more to Apr
30, 2003; Estimated remaining visits: 3 total to be done May and June 2003.   
1,280.00                                   93,440.00    93,440.00 REMOVE:
Unmasked Visits North America:                                              

Canadian

   900.00    10,800.00    (10,800.00 )   0.00              0.00          

U.S.

   1,080.00    68,040.00    (68,040.00 )   0.00              0.00          

 

Page 7 of 15

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     Unit Cost

--------------------------------------------------------------------------------

   Original
Study Total

--------------------------------------------------------------------------------

   Adjustment
Amendment
2

--------------------------------------------------------------------------------

   Revised
Study Total
($US)

--------------------------------------------------------------------------------

   Adjustment
Amendment
3 Occurring
to Nov.
2001

--------------------------------------------------------------------------------

   Adjustment
Amendment
3 Occurring
post Nov.
2001

--------------------------------------------------------------------------------

   Revised
Study Total
($US)

--------------------------------------------------------------------------------

   Adjustment
Amendment
4

--------------------------------------------------------------------------------

    Revised
Study Total
($US)

--------------------------------------------------------------------------------

              Amendment
2

--------------------------------------------------------------------------------

         Amendment
#3

--------------------------------------------------------------------------------

     Amendment
#4

--------------------------------------------------------------------------------

AMENDMENT 3 Umasked Visits Australia - initial 6 visits for 6 sites performed
and billed at regular monitoring rate for Australia (same rate of $1280). ADD
Add’l 6 visits for 6 sites requested by ISTA    1,280.00                  
7,680.00         7,680.00          7,680.00

AMENDMENT 3

ADD: Staff Training Australia - Unmasked Monitoring Procedures:

   1,000.00                   1,000.00         1,000.00          1,000.00 Close
Out Visits:                                              

Canadian

   900.00    10,800.00         10,800.00              10,800.00    (10,800.00 )
  0.00

U.S.

   1,080.00    81,000.00         81,000.00              81,000.00    (81,000.00
)   0.00

Australia

   960.00    9,600.00         9,600.00              9,600.00    (9,600.00 )  
0.00

AMENDMENT #4

ADJUSTMENT: Close-out per visit rate increased by 4 hours/visit for visits
occurring between Sept 11, 2001 and Nov 30, 2002 due to increased travel time
related to airport security measures. Number of units adjusted to reflect actual
close-outs required.

Effective Dec 1, 2002 CRAs reallocated to reduce travel time to pre-Sept 11,
2001 allowance of 4 hours/visit, with ISTA assuming responsibility for visits to
sites requiring additional travel. PRA will monitor 9 Canadian sites, 8 US
sites, and 5 Australian sites to June 30, 2003.

                                             

 

Page 8 of 15

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     Unit Cost

--------------------------------------------------------------------------------

   Original
Study Total

--------------------------------------------------------------------------------

   Adjustment
Amendment
2

--------------------------------------------------------------------------------

    Revised
Study Total
($US)

--------------------------------------------------------------------------------

   Adjustment
Amendment
3 Occurring
to Nov.
2001

--------------------------------------------------------------------------------

   Adjustment
Amendment
3 Occurring
post Nov.
2001

--------------------------------------------------------------------------------

   Revised
Study Total
($US)

--------------------------------------------------------------------------------

   Adjustment
Amendment
4

--------------------------------------------------------------------------------

   Revised
Study Total
($US)

--------------------------------------------------------------------------------

             Amendment
2

--------------------------------------------------------------------------------

         Amendment
#3

--------------------------------------------------------------------------------

      Amendment
#4

--------------------------------------------------------------------------------

Canada: 0 pre-Sept 11/01; 1 post-Sept 11/01 to Nov 30/02 @$1200; 9 remaining to
be charged at $900/visit based on assumption that CRA allocations can be revised
to reduce travel time to four hours/visit.

 

US: 5 pre-Sept 11/01 @ $1080; 6 post-Sept 11/01 to Nov 30/02 @ $1440; 8
remaining to be charged at $1080/visit based on assumption that CRA allocations
can be revised to reduce travel time to four hours/visit.

 

Australia: 3 close-outs to Nov 30/02; 5 remaining.

                                             

Canadian:

   1,200.00                                   1,200.00    1,200.00      900.00
                                  8,100.00    8,100.00

U.S.

   1,080.00                                   5,400.00    5,400.00      1,440.00
                                  8,640.00    8,640.00      1,080.00            
                      8,640.00    8,640.00

Australia

   960.00                                   7,680.00    7,680.00

REMOVE: Site Audits

   2,500.00    125,000.00    (125,000.00 )   0.00              0.00          

Australia Investigator Meeting

   12,000.00    12,000.00          12,000.00              12,000.00        
12,000.00

Study Training

   24,550.00    24,550.00          24,550.00              24,550.00        
24,550.00 ADD: Training for Protocol Amendment, new CRFs, rescue data – CRAs and
at sites – 2 hours per site.                                              

 

Page 9 of 15

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     Unit Cost

--------------------------------------------------------------------------------

   Original
Study Total

--------------------------------------------------------------------------------

   Adjustment
Amendment
2

--------------------------------------------------------------------------------

   Revised
Study Total
($US)

--------------------------------------------------------------------------------

   Adjustment
Amendment
3 Occurring
to Nov.
2001

--------------------------------------------------------------------------------

   Adjustment
Amendment
3 Occurring
post Nov.
2001

--------------------------------------------------------------------------------

   Revised
Study Total
($US)

--------------------------------------------------------------------------------

   Adjustment
Amendment
4

--------------------------------------------------------------------------------

   Revised
Study Total
($US)

--------------------------------------------------------------------------------

              Amendment
2

--------------------------------------------------------------------------------

         Amendment
#3

--------------------------------------------------------------------------------

      Amendment
#4

--------------------------------------------------------------------------------

($75x 2hr x 11 sites) Canadian

   150.00         1,650.00    1,650.00              1,650.00         1,650.00

($90x 2 hr x 58 sites) U.S.

   180.00         10,440.00    10,440.00              10,440.00        
10,440.00

AMENDMENT 4

ADD: Additional training, previously invoiced July 1999.

   6,300.00                                  6,300.00    6,300.00

SAE Management

   300.00    81,600.00         81,600.00              81,600.00        
81,600.00

AMENDMENT 2

ADD: SAE Management Estimate of 272 additional SAEs representing an overall 80%
SAE rate for the study.

   500.00         136,000.00    136,000.00              136,000.00        
136,000.00

AMENDMENT 4

ADD: SAE Management: 687 additional SAEs processed to April 30, 2003 (1231 total
to April 30, 2003, less 544 included up to and including amendment 2) plus 19
projected to occur to end of study (estimated study total = 1250).

   500.00                                  353,000.00    353,000.00

Database Design

   13,500.00    13,500.00         13,500.00              13,500.00        
13,500.00

AMENDMENT 2

ADD: Additional 50 hours at $75/hr for creation & distribution of new CRF forms
(BCVA & Efficacy)

             3,750.00    3,750.00              3,750.00         3,750.00

Data Entry:

                                            

1/3 Data Entered

   50,000.00    50,000.00         50,000.00              50,000.00        
50,000.00

2/3 Data Entered

   50,000.00    50,000.00         50,000.00              50,000.00        
50,000.00

3/3 Data Entered

   50,000.00    50,000.00         50,000.00              50,000.00        
50,000.00

 

Page 10 of 15

--------------------------------------------------------------------------------

     Unit Cost

--------------------------------------------------------------------------------

   Original
Study Total

--------------------------------------------------------------------------------

   Adjustment
Amendment
2

--------------------------------------------------------------------------------

   Revised
Study Total
($US)

--------------------------------------------------------------------------------

   Adjustment
Amendment
3 Occurring
to Nov.
2001

--------------------------------------------------------------------------------

   Adjustment
Amendment
3 Occurring
post Nov.
2001

--------------------------------------------------------------------------------

   Revised
Study Total
($US)

--------------------------------------------------------------------------------

   Adjustment
Amendment
4

--------------------------------------------------------------------------------

    Revised
Study Total
($US)

--------------------------------------------------------------------------------

              Amendment
2

--------------------------------------------------------------------------------

         Amendment
#3

--------------------------------------------------------------------------------

     Amendment
#4

--------------------------------------------------------------------------------

AMENDMENT 2

ADD: Data Management Services relating to extra visit, all pts, at 18 months
Original contract per page value of $4/pg x 8 pgs x 1190 pts. May 15 03: 3,015
pgs in house, expecting 500 more, total 3,515 @ $4

   4.00         38,080.00    38,080.00              38,080.00    (38,080.00 )  
  AMENDMENT 4: At May 15, 2003, 3,015 pgs inhouse; expecting 500 more for a
total of 3,515 pgs @ $4/page    4.00                                  14,060.00
    14,060.00

AMENDMENT 3

ADD: Additional Data Management Services based on 5 add’l pt. Visits x 9 pages x
1190 pts x $10 per page.

AMENDMENT 4: ADJUST 2003 CRF PAGES EXPECTED: Data management services for
projected 10,500 pages to be received in 2003 (3 patient visits x 5 pages/visit
x 700 patients) x $10 per page. May 15/03: Now 3,852 pgs in house. 3,000 more
expected total: 6852 @ $10

   10.00                   12,610.00    522,890.00    535,500.00    (466,980.00
)   68,520.00 ADD: Additional Coding Requirements “Other Procedures” performed
to date (Nov/01): Clinical Review Dept & Physician : 48 hours x $95/hr plus 2
hrs x $250/hr    5,060.00                   5,060.00         5,060.00         
5,060.00

 

Page 11 of 15

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     Unit Cost

--------------------------------------------------------------------------------

   Original
Study Total

--------------------------------------------------------------------------------

   Adjustment
Amendment
2

--------------------------------------------------------------------------------

   Revised
Study Total
($US)

--------------------------------------------------------------------------------

   Adjustment
Amendment
3 Occurring
to Nov.
2001

--------------------------------------------------------------------------------

   Adjustment
Amendment
3 Occurring
post Nov.
2001

--------------------------------------------------------------------------------

   Revised
Study Total
($US)

--------------------------------------------------------------------------------

   Adjustment
Amendment
4

--------------------------------------------------------------------------------

   Revised
Study Total
($US)

--------------------------------------------------------------------------------

              Amendment
2

--------------------------------------------------------------------------------

         Amendment
#3

--------------------------------------------------------------------------------

      Amendment
#4

--------------------------------------------------------------------------------

ADD: Clinical Data Review Process: 1 hour per pt x approx. 1013 pts x $95/hour
   96,235.00                   96,235.00         96,235.00         96,235.00
ADD: SAE Page QC Review: 150 hours x $95/hour    14,250.00                  
12,825.00    1,425.00    14,250.00         14,250.00

AMENDMENT 4: ADD:

Scanning support provided April 2002, invoiced previously.

   2,352.00                                  2,352.50    2,352.50 AMENDMENT 4:
ADD: Out of scope CRF Printing services performed January 2001 - April 2003.   
7,035.00                                  7,035.00    7,035.00

AMENDMENT 4: ADD: Additional Clinical Review Queries written by ISTA, processed
by CroMedica:

120 hours x $95/hr.

   11,400.00                                  11,400.00    11,400.00 AMENDMENT:
4 ADD: Processing “True Copy” pages: Estimated 5,000 pages will require
individual manual check against pages in file and DCFs in file, and data
cleaning, projected to June 30, 2003.    Incremental
effort over
normal
processing =
$13.50/page.                                            13.50                  
               67,500.00    67,500.00 Project Management Fees                  
                           (per month for 25 months - rate reflects absorption
of fees in up front payment)    5,566.00    139,150.00         139,150.00     
        139,150.00         139,150.00 ADD: 15 add’l months (extended to
September, 2002)    18,075.00         271,125.00    271,125.00             
271,125.00         271,125.00 AMENDMENT 3 ADD: 39 months    10,000.00          
             390,000.00    390,000.00         390,000.00

 

Page 12 of 15

--------------------------------------------------------------------------------

     Unit Cost

--------------------------------------------------------------------------------

   Original
Study Total

--------------------------------------------------------------------------------

   Adjustment
Amendment
2

--------------------------------------------------------------------------------

   Revised
Study Total
($US)

--------------------------------------------------------------------------------

   Adjustment
Amendment
3 Occurring
to Nov.
2001

--------------------------------------------------------------------------------

   Adjustment
Amendment
3 Occurring
post Nov.
2001

--------------------------------------------------------------------------------

   Revised
Study Total
($US)

--------------------------------------------------------------------------------

   Adjustment
Amendment 4

--------------------------------------------------------------------------------

    Revised
Study Total
($US)

--------------------------------------------------------------------------------

                Amendment
2

--------------------------------------------------------------------------------

         Amendment
#3

--------------------------------------------------------------------------------

     Amendment
#4

--------------------------------------------------------------------------------

  October, 2002 - March, 2005 and monthly payment to be revisited to establish
continued level of effort for Project Management (study extended to December,
2005)    10,000.00                                  (370,000.00 )   (370,000.00
) AMENDMENT 4 REMOVE: Project Management beyond December 2003. ADJUST: Project
Management fees for December 2002 to 12,307.69 (based on original agreement with
Lisa Grillione of $160,000 for 13 months, Dec 02 to Dec 03)    12,307.69        
                         12,307.69     12,307.69   Amendment 4 adj: remove Jan
03 to Dec 03 @ 12,037.69. Should be @ $15,000 per month to July 31/03 as agreed
with Lisa Grillione Dec 9 2002 if study wrapped up.    12,307.69               
                            Note: It was also agreed that should ISTA opt to
close out study in April 2003 instead of December, monthly project management
fees of $15,000 will apply from January 1, 2003 to July 31, 2003. Should the
study extend beyond July 31, 2003 additional charges to be determined at that
time will apply. Work will not extend beyond July 31, 2003 without a signed
change order in place.    15,000.00                                  105,000.00
    105,000.00  

 

Page 13 of 15

--------------------------------------------------------------------------------

     Unit Cost

--------------------------------------------------------------------------------

   Original
Study Total

--------------------------------------------------------------------------------

   Adjustment
Amendment
2

--------------------------------------------------------------------------------

   Revised Study
Total ($US)

--------------------------------------------------------------------------------

   Adjustment
Amendment
3 Occurring
to Nov. 2001

--------------------------------------------------------------------------------

   Adjustment
Amendment 3
Occurring post
Nov. 2001

--------------------------------------------------------------------------------

   Revised Study
Total ($US)

--------------------------------------------------------------------------------

   Adjustment
Amendment 4

--------------------------------------------------------------------------------

    Revised Study
Total ($US)

--------------------------------------------------------------------------------

              Amendment 2

--------------------------------------------------------------------------------

         Amendment #3

--------------------------------------------------------------------------------

     Amendment #4

--------------------------------------------------------------------------------

AMENDMENT 3 ADD: Senior Management Services - Dr. Wayne Davis 6 hrs/ wk x 19
weeks to end of 2001 x $250/hour    28,500.00                   28,500.00     
   28,500.00          28,500.00 Enrollment Tracking:    2,519.71    120,946.00
        120,946.00              120,946.00          120,946.00 Effective
October, 2000 - $2,519.71 per month for 48 months. All work has been completed.
Total Invoiced to Mar 31/03: 75,591.30. Balance of $45,354.70 to be invoiced
upon execution of Amendment 4                                              
AMENDMENT 4 ADD: Enrollment tracking only for 25 weeks extended enrollment
@$655/week.    16,375.00                                  16,375.00    
16,375.00 AMENDMENT 3 ADD: Australia 38 hours to May, 2001 to address Drug &
Saline Expiration Issue    3,760.00                   3,760.00         3,760.00
         3,760.00 AMENDMENT 4 Add: SAE Hard Copy, based on total estimated SAEs
of 1,250. Calculated as: Drug Safety: .08 hrs per SAE plus 16 hours @ US$120/hr
for Drug Safety personnel and .08 hrs per SAE @ US$68/hr for Project Assistant
or $16.58 per SAE    16.58                                  20,725.00    
20,725.00

AMENDMENT 4 Add: 1.5

hrs CD @ $102/hr and 1.5 hrs DP @ $128/hr for updating validation checks to
include “V 12 done/Patient Completion” check.

   345.00                                  345.00     345.00

Total Contract

        2,938,571.00    934,245.00    3,872,816.00    343,110.00    1,658,465.00
   5,874,391.00    (1,318,832.81 )   4,555,558.19

 

Page 14 of 15

--------------------------------------------------------------------------------

Unit Cost

--------------------------------------------------------------------------------

   Original
Study Total

--------------------------------------------------------------------------------

   Adjustment
Amendment
2

--------------------------------------------------------------------------------

  

Revised

Study Total
($US)

--------------------------------------------------------------------------------

   Adjustment
Amendment
3 Occurring
to Nov.
2001

--------------------------------------------------------------------------------

   Adjustment
Amendment
3 Occurring
post Nov.
2001

--------------------------------------------------------------------------------

   Revised
Study Total
($US)

--------------------------------------------------------------------------------

   Adjustment
Amendment
4

--------------------------------------------------------------------------------

  

Revised

Study Total
($US)

--------------------------------------------------------------------------------

         Amendment
2

--------------------------------------------------------------------------------

         Amendment
#3

--------------------------------------------------------------------------------

      Amendment
#4

--------------------------------------------------------------------------------

Pass-through Costs: SPONSOR shall reimburse CONTRACTOR for reasonable
pass-through costs (e.g., travel, lodging, meals) at net thirty (30) days term
upon receipt of original receipt(s)/invoice. Interest at 15% shall apply if net
thirty (30) days terms are not satisfied. Additional Service Fees: This
amendment includes estimated services up to July 31, 2003. PRA will not
undertake further work beyond July 31, 2003 without a signed changeorder.

 

Page 15 of 15