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[NOTE: CERTAIN PORTIONS OF THIS DOCUMENT HAVE BEEN MARKED TO INDICATE THAT
CONFIDENTIALITY HAS BEEN REQUESTED FOR THIS CONFIDENTIAL INFORMATION. THE
CONFIDENTIAL PORTIONS HAVE BEEN OMITTED AND FILED SEPARATELY WITH THE SECURITIES
AND EXCHANGE COMMISSION.]
EXHIBIT 10.39
[ ALTEON LETTERHEAD ]
AMENDMENT TO
CLINICAL SERVICES AGREEMENT
THIS AMENDMENT TO CLINICAL SERVICES AGREEMENT (this "Amendment") is
entered into as of this 15 day of July 1998, by and between Alteon Inc., a
Delaware corporation, with offices at ▇▇▇ ▇▇▇▇▇▇▇▇ ▇▇▇▇▇, ▇▇▇▇▇▇, ▇▇▇ ▇▇▇▇▇▇
▇▇▇▇▇ ("ALTEON"), and Quintiles, Inc., a North Carolina corporation, with
offices at ▇▇▇▇ ▇▇▇▇▇▇ ▇▇▇▇, ▇▇▇▇▇▇, ▇▇▇▇▇ ▇▇▇▇▇▇▇▇ ▇▇▇▇▇ ("QUINTILES") (each of
ALTEON and QUINTILES, a "Party" and collectively, the "Parties").
PRELIMINARY STATEMENTS
A. The Parties previously entered into that certain Clinical Services
Agreement, dated as of August 11, 1996 (the "Agreement").
B. The parties wish to amend the scope of the Services to be provided
by Quintiles under the Agreement, upon the terms and conditions set forth in
this Amendment.
C. Pursuant to Section 5.1 of the Agreement, Attachment C thereto set
forth the total estimated budget for the Services to be performed by QUINTILES
under the Agreement which has subsequently been modified by the process detailed
in Sections 1.2(p) and 5.9.
D. Section 5.1 of the Agreement contemplates that the Parties may amend
the Budget from time to time, upon the agreement of the Parties.
E. In addition to expanding the Scope of the Services, the Parties wish
to establish fixed terms of the Budget with respect to the Services that
QUINTILES has performed and will perform under the Agreement and the means by
which such Budget terms with respect to the Studies under Protocols Numbers
AGPR0002 and AGPR0009, PR0016, PR0014, IND Annual Safety Report preparation (the
"Subject Studies"), and preparation and management of the NDA application for
the Compound under Protocol Number AGPR0002 (the "NDA Preparation"), may be
adjusted in the future, all upon the terms and conditions set forth in this
Amendment.
NOW, THEREFORE, in consideration of the Preliminary Statements and the
mutual covenants and promises set forth in this Amendment, the Parties hereby
agree to amend the Agreement as follows:
1. Revised Budget and Time Lines. The Budget is hereby amended as
reflected in Attachment A attached. The Parties acknowledge and agree that such
Budget, as so amended, shall constitute the final Budget, subject to the Budget
Adjustments set forth in Section 4 of this Amendment, unless such Budget is
further amended pursuant to Sections 1.2(p) and 5.9 of the Agreement. QUINTILES
estimates that its actual cost to complete the Subject Studies is
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approximately $* in excess of the total amount stated in the Budget attached
hereto as Attachment A. In consideration of QUINTILES' agreement to the reduced
total amount stated in the Budget, ALTEON agrees to waive any right it may have
to dispute the costs, fees and expenses previously invoiced by QUINTILES, and
releases any over-payment or over-billing claims it may have regarding such
costs, fees and expenses. ALTEON acknowledges that the Budget attached hereto as
Attachment A supersedes all prior estimates or agreements, oral or written,
regarding the amount of costs, fees and expenses that shall be paid pursuant to
the Agreement and this Amendment. In addition, the time lines applicable to the
Agreement are hereby amended as reflected in Attachment A attached hereto, which
supersedes all prior estimated or agreed time lines regarding the Agreement and
this Amendment.
2. Amendment of Section 5.2. The first sentence of Section 5.2 of the
Agreement hereby is amended such that, following such amendment, such sentence
is replaced in its entirety as follows:
"ALTEON shall pay to QUINTILES the fees and other
out-of-pocket costs set forth in the Budget. ALTEON shall not
be required to make payments with respect thereto that are in
excess of the amounts set forth in the Budget, except to the
extent that ALTEON previously shall have approved such excess
fees and costs."
3. No Further Automatic Budget Adjustments. From and after the date of
this Amendment Section 5.8 of the Agreement is no longer applicable and there
shall be no adjustment of the Budget under such Section 5.8. Any future
adjustments to the Budget shall be effected using the procedure set forth in
Section 5.9 of the Agreement, regardless of the magnitude thereof, except as set
forth in Section 4 of this Amendment. With respect solely to the Services to be
provided by QUINTILES in connection with the NDA Preparation, ALTEON agrees that
it will not unreasonably withhold approval of a cost increase, even if it
involves a fixed price Service, if the proposed changes in budgets or time lines
result from, among other appropriate reasons, forces outside the reasonable
control of QUINTILES or changes in the assumptions upon which the initial budget
or time lines were based. QUINTILES reserves the right to postpone effecting any
future material increases in the scope of the Services until such time as the
parties agree to and execute a written amendment or change order by the process
detailed in Sections 1.2(p) and 5.9.
4. Certain Budget Adjustments with Respect to Subject Studies under
Protocols Numbers AGPR0002 and AGRP0009.
4.1 In the event that the number of days of on-site clinical
monitoring reasonably required to complete the Services with respect to each of
the Subject Studies after January 31, 1998, is greater or less than the number
of the remaining days of such visits forecast in Attachment A, the applicable
line item in the Budget shall be appropriately adjusted, at a rate of $* per day
(adjusted in increments of one-half days). Likewise, in the event the number of
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clinical monitoring visits required to complete the Services with respect to
each of the Subject Studies after January 31, 1998 is greater or less than the
remaining number of such visits forecasts in Attachment A, the applicable line
item in the Budget shall be appropriately adjusted at a rate of 1.4 days per
visit for travel time, trip planning, and report writing, at a rate of $* per
day. Monitoring Travel miscellaneous cost will be considered a variable direct
pass-through expense which will be reconciled at the end of this project.
4.2 In the event that the number of SAEs reasonably required
to be processed to complete the Services with respect to each of the Studies
after January 31, 1998, is greater or less than the number of the remaining such
SAEs forecast in Attachment A, the applicable line item in the Budget shall be
appropriately adjusted, at a rate of $* per SAE.
4.3 In the event that the number of CRF pages reasonably
required to be tracked to complete the Services with respect to each of the
Subject Studies after January 31, 1998, is greater or less than the number of
the remaining such pages forecast in Attachment A, the applicable line item in
the Budget shall be appropriately adjusted, at a rate of $* per page.
4.4 In the event that the number of pages reasonably required
to be entered into the databases and audited to complete the Services with
respect to each of the Subject Studies after January 31, 1998, is greater or
less than the number of such pages forecast in Attachment A, the Budget shall be
appropriately adjusted, at a rate of $* per page (i.e., six minutes per page, at
$* per minute) with respect to the Subject Study under Protocol Number AGPR0002,
and $* per page (i.e., seven minutes per page, at $* per minute) with respect to
the Subject Study under Protocol Number AGPR0009.
4.5 ALTEON shall pay QUINTILES the amounts stated in the
Budget according to the Payment Schedule attached hereto as Attachment B. Only
the unit-based items referenced in Sections 4.1, 4.2, 4.3 and 4.4 above and
variable expense as defined in each project budget shall be subject to upward or
downward adjustments, unless the Agreement is modified pursuant to its Sections
1.2(p) or 5.9. Upon ALTEON's request from time to time, and, in any event,
within 30 days after the completion of the Services, QUINTILES shall provide
ALTEON with written evidence of the then current number of the respective units
referred to in this Section 4 which QUINTILES has consumed. All adjustments to
the Budget pursuant to this Section 4 shall be made in connection with ALTEON's
final payment under the Budget; provided, however, that if the aggregate effect
of adjustments under this Section 4 reduces the amount of such final payment
below zero, QUINTILES shall pay ALTEON the amount necessary to make up such
deficiency within 30 days after the completion of the Services.
4.6 Fixed Price Revisions. The following provisions are no
longer applicable due to the fixed price/fixed unit price nature of the
Agreement, as amended: Section 3.2(b); the second and third sentences of Section
5.1; the second, third and fourth sentences of Section 5.3; the clause at the
end of Section 5.4 stating "and supplemental information (as contemplated by
Section 5.3)"; Section 5.6; the last clause of Section 5.10 stating "and in
sufficient detail to
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permit ALTEON to confirm the accuracy of the invoices submitted pursuant to this
Section 5"; and Section 5.11.
5. Scope of Work Amendment. Simultaneously with the execution of this
Amendment, the Parties will execute a scope of work amendment to the Agreement,
pursuant to which QUINTILES shall undertake the NDA Preparation, at a total
agreed-to budget of $*. The Payment Schedule for such work is attached hereto as
Attachment B.
6. Personnel Change. Due to ▇▇▇▇▇ ▇▇▇▇▇▇▇▇'▇ departure, Section 1.3(b)
of the Agreement is no longer applicable, and the name "▇▇▇▇▇ ▇▇▇▇▇▇▇▇" is
hereby replaced by "▇▇▇ ▇▇▇▇▇▇" in Sections 1.3(b) and 1.5(b).
7. Capitalized Terms. All capitalized terms not otherwise defined in
this Amendment shall have the respective meanings assigned thereto in the
Agreement.
8. Continuing Effect of Agreement. Except as amended herein, in all
other respects the Agreement shall remain in full force and effect and be
unaffected by this Amendment.
* * *
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IN WITNESS WHEREOF, each of the Parties has caused its duly authorized
representative to execute this Amendment as of the date first set forth above.
ALTEON INC.
By: /s/ ▇▇▇▇▇▇▇ ▇. ▇▇▇▇
-------------------------------
Name: ▇▇▇▇▇▇▇ ▇. ▇▇▇▇
----------------------------
Title: CFO
--------------------------
QUINTILES, INC.
By: /s/ ▇▇▇▇▇ ▇. ▇▇▇▇▇▇▇▇
------------------------------
▇▇▇▇▇ ▇. ▇▇▇▇▇▇▇▇
Vice President, Business Development
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ATTACHMENT A
REVISED FINAL BUDGET
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AMENDMENT TO THE CLINICAL SERVICES AGREEMENT
Attachment A: Budget for Protocols AGPR002 and AGPR009
PROJECT SET-UP INITIATION
Project Transfer and Start-Up *
Development of Study Files *
CRA Meeting *
SUBTOTAL PROJECT SET-UP AND INITIATION: *
CLINICAL TRIAL MANAGEMENT
Clinical Monitoring - Interim, Close-Out Visits *
Clinical In-House Administration *
Drug Distribution Management *
SUBTOTAL CLINICAL TRIAL MANAGEMENT *
MEDICAL SUPPORT
AE Processing and Reporting *
SUBTOTAL MEDICAL SUPPORT: *
CLINICAL DATA MANAGEMENT
Database Design and Maintain *
CRF Tracking *
Edit Specifications, Pre-Entry Edit, DCF Queries Resolution *
Data Entry, Database Audit *
Coding - Disease, Medication, Adverse Events *
SUBTOTAL CLINICAL DATA MANAGEMENT *
BIOSTATISTICAL ANALYSIS
Annotated Report Outline *
Statistical Integrated Study Report *
SUBTOTAL BIOSTATISTICAL ANALYSIS *
SUPPORT SERVICES
Project Management *
Administrative Support *
Client Meetings *
SUBTOTAL SUPPORT SERVICES: *
TOTAL QUINTILES FEES *
MISCELLANEOUS COSTS
Monitoring Travel *
Client Meeting Travel *
CRA Meeting Travel *
Computer Support *
Copying, Printing, Postage, Telephone, Supplies *
Videoconferencing *
SUBTOTAL MISCELLANEOUS COSTS *
GRAND TOTAL *
LESS QUINTILES CONSIDERATION *
ADJUSTED TOTAL *
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AMENDMENT TO CLINICAL SERVICES AGREEMENT
ATTACHMENT A
BUDGET NOTES - PROTOCOL NUMBERS AGPR002 AND AGPR009
(PIMA010 AND PIMA020)
The following variable expense units are defined under this project:
CLINICAL TRIAL MANAGEMENT
Clinical Monitoring
PIMA010
Unit Costing:
$* per day for time on site.
Estimate of Time on site to Complete Trial:
25 visits at 2 days on site
145 visits at 3 days on site
49 visits at 1.5 days on site (closeout visits)
Actual time on site to be determined by time sheets
Fixed Amount of 1.4 days per visit for travel time and trip planning and report
writing at $* per day rate
PIMA020
Unit Costing:
$* per day for time on site.
Estimate of Time on Site to Complete Trial:
28 visits at 1.5 days on site
140 visits at 2.0 days on site
71 visits at 1.5 days on site (closeout visits)
Actual time on site to be determined by time sheets
Fixed Amount of 1.4 days per visit for travel time and trip planning and report
writing at $* per day rate
Monitoring Travel miscellaneous cost will be a variable pass-through expense
which will be reconciled at the end of the project.
MEDICAL SUPPORT
AE Processing
PIMA010
Estimate to Complete:
200 SAE's at a unit cost of $*
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AMENDMENT TO CLINICAL SERVICES AGREEMENT
ATTACHMENT A
BUDGET NOTES - PROTOCOL NUMBERS AGPR002 AND AGPR009
(PIMA010 AND PIMA020)
(Based on an average rate of 20 per month for 10 remaining months
(February through November).
PIMA020
Estimate to Complete:
150 SAE's at a unit cost of $*
(Based on an average rate of 25 per month for 6 remaining months
(February through July)
Construction of an estimated 300 Total Cardiovascular files (estimated
$*)
170 are completed
130 estimated new cases in remaining months
CLINICAL DATA MANAGEMENT
CRF Tracking
PIMA010
Estimate to Complete:
29,000 pages remaining at a unit cost of $*
PIMA020
Estimate to Complete:
11,210 pages remaining at a unit cost of $*
DATA ENTRY, DATABASE AUDIT
PIMA010
Estimate to Complete:
29,000 pages remaining at a unit cost of $*
PIMA020
Estimate to Complete
11,750 pages remaining at a unit cost of $*
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AMENDMENT TO CLINICAL SERVICES AGREEMENT
Attachment A: Budget for
SAE Reporting for Protocol PRO014 and PRO016
MEDICAL SUPPORT
AE Processing and Reporting *
SUBTOTAL MEDICAL SUPPORT *
TOTAL QUINTILES FEES *
MISCELLANEOUS COSTS
Computer Support, Copying, Printing, Shipping *
SUBTOTAL MISCELLANEOUS COSTS *
GRAND TOTAL *
The above calculations were based on an average of 11 serious adverse events
reported monthly. It is assumed that reporting of events will continue for
another 18 months (March 1998 through August 1999). This yields a total of 198
more Serious Adverse Events to process at a cost of $* per SAE. Allowance for an
extension study or safety evaluation phase has not been included. Note: Alteon
has been adding investigator sites for the 014 Protocol in the recent months.
This increase in investigator sites may result in an increase in the monthly
reporting rate.
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AMENDMENT TO CLINICAL SERVICES AGREEMENT
Attachment A: Budget for Annual Safety IND Report
Regulatory *
Med. Ops *
Rep. Coordin *
Stat Program *
Biostats *
RDQC *
TOTALS *
Contract Modification signed May 21, 1997
Scope of Work: to prepare three (3) annual safety IND update reports (for years
1997, 1998, and 1999). The cost for the second and third report was budgeted at
a lower rate than the first based on the assumption that the second and third
reports will be identical in content and structure as the first report. Two of
the three reports have been prepared. It is assumed that the scope of the IND
report for 1999 will remain the same as in previous years.
Information on percentage and workcode breakdown provided by ▇▇▇▇▇ ▇▇▇▇▇ (x1463)
on Aug. 4, 1997
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AMENDMENT TO CLINICAL SERVICES AGREEMENT
Attachment A: Budget for the NDA Preparation for Pimagedine
NDA PREPARATION
o Table of Contents *
o Application Summary (Clinical Section only) *
o CMC *
o Labeling *
o Non-Clinical Pharmacology and Toxicology *
o Human PK and Bioavailability and Clinical Pharmacology *
o Microbiology *
o Overall Clinical Summary *
o Clinical Pharmacology *
o Individual Study Reports
Action I Study Report *
Action II Study Report *
o Patent Narratives *
o Integrated Summary of Safety (Integrated database creation,
Analysis and Tables) *
o Integrated Summary of Efficacy (Analysis and Tables) *
o Integrated Summary of Benefits & Risks *
o Safety Update Report (See Optional Costs category on next page) *
o Statistical Methods Section (ISS Methods Insert) *
o CRF Tabulations (See Optional Costs category on next page) *
o Case Report Forms *
o Patent Information and Certification *
o NDA Compilation & Cross Referencing *
o Project Management (includes Administrative Support) *
o Clinical Pharmacology Support *
Sub-Total NDA Preparation *
CONTINUED ON THE NEXT PAGE
Other Services
o NDA Strategy/Pre-NDA Meeting *
o Other Services:
Expert Consulting-Biostatistics, Clinical Sciences and Regulatory Services *
Face to Face Client Meetings (6 meetings; 6 attendees at each) *
Teleconference Client Meetings (Weekly; 8 attendees at each) *
Project Startup and Planning *
Sub-Total Other Services *
Total Services *
Miscellaneous Costs
o Travel
Client Meetings *
6 meetings at Alteon, 6 attendees at each meeting
Pre-NDA Meeting *
o Telephone, Supplies, and Computer Support *
o Shipping of NDA Volumes
Hand Delivery of NDA to FDA (based on 2 copies of 90 volume submission) *
Federal Express Delivery of remaining 4 copies of 90 volume application
to Alteon *
Sub-Total Miscellaneous Costs *
TOTAL NDA BUDGET COST *
OPTIONAL COSTS (Not Included in Total Budget Costs)
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o Safety Update Report *
o CRF Tabulations *
o Action II efficacy tables and text in ISE *
Subtotal Optional Costs *
Total Costs including Optional Costs *
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AMENDMENT TO CLINICAL SERVICES AGREEMENT
ATTACHMENT A
BUDGET NOTES - NDA PREPARATION OF PIMAGEDINE
As described in the proposal for "Revised Scope of Work for New Drug Application
Services and Action I & Action II Final Study Reports" dated July 1, 1998
("Proposal), Quintiles' scope of work for the NDA Preparation for Pimagedine
includes Regulatory Affairs Consulting, Clinical Sciences, Biostatistics,
Programming, QC, and Project Management services. Assumptions are based on
discussions between Quintiles and Alteon. Deviations in these assumptions may
require a modification to the budget and/or timelines.
GENERAL NOTES
Quintiles' participation in this project is based on * consecutive
months beginning *. Should the time line increase/decrease, the budget
will be adjusted accordingly.
The budget is based on Quintiles' 1998 daily rates. If the Services
hereunder last longer than one (1) year, Quintiles' costs may be
increased at the beginning of each year, commencing one year after the
date the Agreement is executed, to reflect increases or decreases in
Quintiles' costs on a prospective basis only. Quintiles' costs may be
increased or decreased for the next twelve (12) month period using the
percentage change in the wages/earnings survey as published in The
Economist for the applicable currencies over the preceding twelve (12)
month period.
Any costs associated with audits performed by Alteon at Quintiles'
facilities will be invoiced to Alteon at cost.
BIOSTATISTICAL AND CLINICAL SCIENCES SERVICES
Costs for error resolution for the following data to be received from
external vendors have not been included in the budget: Covance
laboratory data, Scripps Labs' data, Fundus photography data
(University of Wisconsin, Madison), GFR data (from Covance), the
Quality of Life data (from ▇▇▇▇▇▇ Associates), and plasma pimagedine
data (from Alteon).
Quintiles has assumed that a final transfer of all data from each
vendor will be received as locked databases no later than * for the
Action I study and no later than * for the Action II study. Quintiles
assumes that at least 2 interim transfers of each of these databases
will be received (at approximately * months prior to the last patient
visit and at * months prior to the last patient visit for the Action I
study and at
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approximately * weeks and * weeks prior to the last patient visit for
the Action II study). Quintiles will carry out checks prior to database
lock to determine and seek error resolution for any systematic problems
or inconsistencies found in each of these databases. However, it is
assumed that final responsibility for locking each vendor database will
reside with each individual vendor. Any additional costs incurred by
Quintiles as a result of errors or inconsistencies in any of the
databases delivered to Quintiles as a locked database will be billed on
a fee-for-service basis. This will include costs for re-running
analysis files or tables.
Quintiles has assumed that no changes to the definition of the Per
Protocol population will take place after database lock. Any costs (due
to re-programming analysis files and re-running tables) as a result of
changes to the definition of the Per Protocol population after database
lock will be billed on a fee-for-service basis.
Quintiles has assumed that adverse events of special interest
(including the exact definition of flu syndrome) for the NDA will have
been defined (or the rule for selecting them has been defined) by *.
Any costs (due to re-programming analysis files and re-running tables)
as a result of changes to the definition of special interest adverse
events after * will be billed on a fee-for-service basis.
Quintiles has budgeted for a data review meeting for the Action I study
and a data review meeting for the Action II study with an anticipated
date of * working days prior to database lock in each case. For these
meetings Quintiles will provide data dumps ( SAS Proc Prints of raw
data) for all CRF data only. In addition, frequencies (for binary
data), and the highest and lowest values as well as quantiles (for
continuous data) will be provided for CRF data on the following
variables: key disposition variables, demographics, the primary
efficacy parameter, adverse events, and key laboratory parameters
(including those which are key secondary parameters). Any outstanding
discrepant dates or other questionable or missing information related
to the primary efficacy parameter will be fully summarized. It is
assumed that no new DCFs will be issued as a result of discussions at
the data review meetings, as otherwise delays are likely to result for
all subsequent deliverables.
Costs to develop the Integrated Summary of Safety(ISS) Annotated Report
Outline(ARO), Integrated Summary of Efficacy(ISE) ARO, Action I ARO,
Action II ARO, ISS Table Shells, ISE Table Shells, ISS Tables, ISE
Tables, Data Listings for Action I and Action II, CRF Tabulations for
Action I and Action II (if no FDA waiver is given), text for the Action
I integrated clinical and statistical study report, text for the Action
II abbreviated integrated clinical and statistical study report, ISE
text, ISS text, text for the remainder of the Clinical Section, text
for the Clinical Data Summary, text for the Risk-Benefit section, and
text for the Statistical Methodology section of the NDA have all been
included in the budget. Those tables to be included in the ISS, the
ISE, the Action I study report, and the Action II abbreviated study
report are specified in Appendices 1 and 2. Estimated costs include one
round of review and incorporation of consolidated comments from Alteon
to create the final version for all Tables, Data
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Listings, CRF Tabulations, Action I ARO, Action II ARO, text for the
Action I study report, ISE text, ISS text, text for the remainder of
the Clinical Section, text for the Clinical Data Summary, and
Statistical Methodology text. Estimated costs for the ISS ARO, the ISE
ARO, Table Shells, and text for the Action II abbreviated study report,
allow for two rounds of review and incorporation of comments. In all
cases it is assumed that Alteon provides one integrated set of comments
(including comments from ▇▇▇▇▇▇ ▇▇▇▇▇▇▇▇▇▇ University and any other
third parties). For the Risk-Benefit section costs assume that
Quintiles will produce one draft version after which Alteon will
finalize the document.
It is assumed that the final SAE documentation (SAE reporting and
source documentation) is received from all investigator sites by * for
the Action I study and * for the Action II study.
Any additional tables, figures, or listings Alteon requires outside of
the approved AROs for the ISS, the ISE, the Action I study, or the
Action II study will be discussed and any additional fees negotiated
with Alteon.
All patient narratives will be prepared by Alteon. Should Alteon
request that Quintiles prepare patient narratives, Quintiles will
provide Alteon a cost estimate for development of patient narratives.
At Alteon's request, Quintiles will send printouts of the concomitant
medication and AE coding mappings on two occasions, once prior to
Action II database lock and once prior to Action I database lock.
Quintiles has assumed that all Quintiles and Alteon reconciliation
between Quintiles' coding dictionaries and the coding dictionaries used
in other studies (including the ESRD study conducted by ACER/EXCEL)
will have taken place prior to Action II database lock. Quintiles
estimated dates for production of the ISE and ISS tables assume that no
changes to coding dictionaries occur after Action II database lock for
terms that are present in Action II, and no changes occur after Action
I database lock for terms that are present in Action I. In addition,
any costs (due to re-running analysis files or tables) as a result of
changes in coding after database lock will be billed on a
fee-for-service basis.
Costs for 10 days of expert consulting each from the Biostatistics,
Clinical Sciences and Regulatory departments have been included in the
budget. Estimated costs are based on daily rates of $* for
Biostatistics; $* for Clinical Sciences and $* for Regulatory. Any
additional expert consultancy above 10 days from any of these
departments will be billed on a fee-for-service basis.
Costs have been included for two (2) Quintiles' attendees (one from
Clinical Sciences and one from Biostatistics) at the Pre-NDA meeting.
Any additional attendees at Alteon's request will be billed to Alteon
on a fee-for-service basis.
Costs have been included for Quintiles' expert review of the text for
the ISS, the ISE, the
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Action I study report, the Action II abbreviated study report, the
remainder of the Clinical Section, the Clinical Data Summary, and the
Risk-Benefit section by Clinical Sciences, the Project Medical Officer
(or another M.D.), Regulatory, and Biostatistics. For the statistical
methodology section and all AROs costs have been included for expert
reviews by Biostatistics, Clinical Sciences, and Regulatory. For tables
and table shells costs include expert review by Biostatistics and
Clinical Sciences. For data listings and CRF tabulations (if required)
costs include expert review by Biostatistics. All expert reviews will
be carried out prior to delivery of these items to Alteon.
Costs are included for a QC review of all deliverables of AROs, table
shells, tables, data listings, CRF tabulations, and text. These QC
reviews will have taken place prior to delivery of the items to Alteon.
Quintiles will generate 399 tables (141 for Action I alone, a further
149 for Action II alone, and a further 109 for Action I and Action II
combined), including 64 unique tables, and 20 figures for the ISS. A
full list of the ISS tables which Quintiles has assumed will be
required is provided in Appendix 1.
Quintiles will generate 85 tables (including 35 unique tables), and 24
figures for the ISE, all of which will be based on Action I alone. A
full list of the ISE tables which Quintiles has assumed will be
required, is provided in Appendix 2.
Quintiles will produce 215 tables for the Action I study report, 86
unique tables, and 33 figures. A total of 211 of these tables and all
figures will be identical (other than header information) to a
corresponding ISS or ISE table. A full list of the Action I tables
which Quintiles has assumed will be required is provided in Appendices
1 and 2.
Quintiles will produce 230 tables for the Action II abbreviated study
report, 88 unique tables, and 32 figures. A total of 153 of these
tables and 11 figures will be identical (other than header information)
to a corresponding ISS table. A full list of the Action II tables which
Quintiles has assumed will be required is provided in Appendices 1 and
2.
Additional analyses outside of the lists of tables provided in
Appendices 1 and 2 can be provided, on a fee-for-service basis.
However, certain additional ISE analyses (including any exploratory
analyses, any reasonable case analysis, and any additional figures) may
take longer than 7 weeks after database lock.
It is assumed that a total of 25 data listings will be produced for the
Action I study and 25 data listings will be produced for the Action II
study.
Quintiles would recommend that Alteon seek a waiver from the FDA for
CRF tabulation production. However, if Alteon does not receive a
waiver, Quintiles estimates that CRF tabulation production for Action I
and Action II would cost approximately $* altogether.
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It is assumed that the statistical methodology section of the NDA will
be at most 60 pages of text (at 1.5 line spacing). Further, it is
assumed to cover only statistical methodology corresponding to analyses
produced by Quintiles in the ISS or ISE, together with analysis
discussion in the text of the ISS or ISE by Quintiles. These methods
will be discussed in the stats trial methodology section of the NDA
based on the methods sections from the corresponding study reports. It
is assumed that statistical methodology for analysis of Quality of Life
and plasma pimagedine will be provided to Quintiles as drop-in
sections.
Quintiles has assumed that no tables from any study other than Action I
and Action II will be required for the ISS and no tables from any study
other than Action I will be required for the ISE. If additional tables
are required from other studies in the ISS or ISE then these will be
billed on a fee-for-service basis. ISS or ISE tables produced from
studies other than Action I and Action II may take longer than those
produced for Action I and II.
Costs include tasks required to produce the key draft ISS tables for
Action I within * weeks of Action I database lock and the remaining
draft ISS tables (except for AE prevalence tables) for Action I will be
delivered in * batches at weekly intervals over the following * weeks.
Costs also include tasks required to produce AE prevalence tables
within a further * weeks. Those tables which correspond to the "key"
ISS text (as defined by Alteon) will be given highest priority.
However, exactly which tables will be included in each of the these *
batches is also dependent on data-driven issues.
Costs include tasks required to produce ISS tables based on Action II
alone in 3 batches with the first delivered within * weeks of Action II
database lock and the last delivered within * weeks of database lock.
Costs for production of the integrated ISS database assume that adverse
events, laboratory data, and ▇▇▇▇▇ ▇▇▇▇▇ is the only safety data that
is fully integrated, and that this is based only on Action I and Action
II. It is further assumed that the only data that is partially
integrated is that part of the demographics, medications, and medical
history needed for the interaction analyses in the ISS and the ISE. It
is assumed that ECGs, efficacy data, and all other data will not be
integrated at all. Quintiles estimates that those ISS tables based on
the integrated database will be submitted to Alteon within * weeks of
the integrated database lock.
Costs for the ISE assume that the last draft table for Action I from
the list specified in Appendix 2 will be produced within * weeks after
Action I database lock (subject to the assumptions set out in this
proposal). Some ISE tables will be delivered in batches prior to this
date, but exactly which tables will be included in any particular batch
is highly dependent on data-driven issues. Those tables corresponding
to the most important efficacy parameters will be given the highest
priority. However, it is anticipated that those analyses based on
survival endpoints (including analysis for the primary efficacy
parameter) will be in a later batch as they are likely to be most
affected by (data-driven) special cases, which arise very shortly
before database lock.
* Confidential Treatment Requested
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Quintiles estimates that any additional safety tables needed for the
Action I or Action II study reports will be produced according to the
timeline (relative to the individual study's database lock) described
above. Likewise Quintiles estimates that any additional efficacy or
other non-safety tables needed for the Action I or Action II study
reports will be produced according to the timeline (relative to the
individual study's database lock) described above.
For the ISE and for the Action II efficacy analyses Quintiles has
assumed that the programs written by ▇▇▇▇▇▇ ▇▇▇▇▇▇▇▇▇▇ University to
produce the ESMC analyses (except for any code that reveals information
that would unblind a patient) will be received electronically by *.
Further, it is assumed that any additional code covering information
related to a patient's treatment assignment, together with all results
from interim analyses will be provided electronically * after
unblinding.
For the ISE, it is further assumed that agreement is reached between
Quintiles, ▇▇▇▇▇▇ ▇▇▇▇▇▇▇▇▇▇ University, and Alteon by * for Action I
and Action II on all analyses and all data analysis rules to be used in
the ISS/ISE, the Action I and Action II study reports, and in the
interim and final analyses to be carried out by ▇▇▇▇▇▇ ▇▇▇▇▇▇▇▇▇▇
University for either study. If different analysis rules are followed
by ▇▇▇▇▇▇ ▇▇▇▇▇▇▇▇▇▇ University or Alteon compared with the rules to be
adopted by Quintiles in the ISE and the ISS, then additional costs will
result for the reconciliation of these results with the results
produced by Quintiles. This will be billed on a fee-for-service basis.
It is assumed that Quintiles writes the Action I Integrated Clinical &
Statistical Study report. The results section is assumed to be based on
the 215 tables specified in Appendices 1 and 2 (85 tables identical to
Action I ISE tables a further 126 tables identical to Action I ISS
tables and 4 additional tables). It is assumed that methods and results
sections covering plasma pimagedine data, (including relationship of
plasma pimagedine to efficacy or safety) and Quality of Life date will
be written by their corresponding vendors or will be written by Alteon,
and it is assumed that these sections will be supplied to Quintiles as
drop-in sections and that these will use section numbering as specified
by Quintiles. Further, it is assumed that text covering results for
Quality of life and plasma pimagedine data for the ISE (and for the ISS
if appropriate) will be supplied as a drop-in section.
It is assumed that Quintiles writes the Action II abbreviated
Integrated Clinical & Statistical Study. The results section is assumed
to be based on the 209 tables specified in Appendices 1 and 2 (153
tables identical to Action II ISS tables, and 77 additional tables). It
is assumed that methods and results sections covering plasma pimagedine
data and Quality of Life will be written by their corresponding vendors
or will be written by, (including relationship of plasma pimagedine to
efficacy or safety) Alteon. It is assumed that these sections will be
supplied to Quintiles as drop-in sections and that these will use
section numbering as specified by Quintiles. Further, it is assumed
that text covering results for Quality of life and plasma pimagedine
data for the ISE (and for the ISS if
* Confidential Treatment Requested
20
appropriate) will be supplied as a drop-in section.
Quintiles has assumed that an integrated set of comments is received
from Alteon within * days of shipment of each batch of ISS or ISE
tables. Further, Quintiles has assumed that draft tables will be
revised to produce final tables as indicated by the integrated comments
from Alteon, within at most * weeks of receipt of comments, except for
the last batch of ISE tables where revised tables will be shipped
within * of receiving comments. This timeline assumes that as a result
of Alteon's comments on each batch of ISS or ISE tables, no new tables
are required, no additions to tables are required, no changes are made
to any definitions, and no additional exploratory analyses are needed.
Quintiles has assumed that Alteon is able to obtain FDA agreement to
the ISS ARO, the ISE ARO, and the data analysis rules for the ISS and
ISE by *. Quintiles also assumes that no additional analyses are
required as a result of the Pre-NDA meeting scheduled for *. If such
additional analyses are required then these will be billed on a
fee-for-service basis and this is likely to impact on the NDA timeline.
Quintiles has assumed that all data on patients who are lost to
follow-up (including any additional data collected as a result of
active searching for these lost to follow-up patients) is received at
Quintiles by * for Action I patients and by * for Action II patients.
Quintiles has assumed that the last DCF for any data retrieved for lost
to follow-up patients is resolved by * for Action I patients and by *
for Action II patients. Any delays in receipt of this information may
lead to delays in all subsequent dates on the timeline.
This budget estimate does not include costs for Quintiles to scan CRFs.
Any support provided by Quintiles in connection with the scanning of
CRFs have not been included in the budget. If required, this support
will be invoiced to Alteon at a daily rate of $*.
In order to lock the database for Action II within * months of the last
patient visit it is assumed that all CRF pages are available be
collected at the last monitoring visit (estimated to be on *). Further,
it is assumed that all DCFs receive a resolution from the sites within
*.
It is assumed that the Action II abbreviated study report will be at
most 120 pages in length (from Introduction to Conclusions based on 1.5
spacing) with 25-30 panels (in-text tables). No cost for patient
narratives has been included, but if it is required for Quintiles to
produce these then they will be charged on a fee-for-service basis.
It is assumed that the Action I study report will be 150-160 pages in
length (from Introduction to Conclusions based on 1.5 spacing) with
30-40 panels (in-text tables). No cost for, patient narratives has been
included, but if it is required for Quintiles to produce
* Confidential Treatment Requested
21
these then they will be charged on a fee-for-service basis.
Quintiles costs and timelines assume that for the ISE only Action I
will be summarized from tables included in the ISE itself. It is also
assumed that the only additional studies summarized in the ISE text
will be Action II and the Dyslipidemia study. Costs for the ISE assume
that there will be 150-200 pages of text (at 1.5 line spacing).
Quintiles has also given separate costs for including tables based on
Action II in the ISE. In this option, such tables would be a subset of
the tables produced for the Action II study report and would differ
from study report only in header information.
Quintiles costs and timelines assume that for the ISS only Action I and
Action II will be summarized from tables included in the ISS itself. It
is also assumed that the only additional studies summarized in the ISS
text will be those studies listed in Appendix 3. Costs for the ISS
assume that there will be 250-300 pages of text (at 1.5 line spacing).
Costs and timelines for the ISE and ISS text writing assume that
Quintiles is not responsible for production of analyses, tables, or
study report text for any studies other than Action I or Action II.
Further, it is assumed that for all studies other than Action I and
Action II a final and complete study report together with a set of
tables is provided to Quintiles by *. In addition it is assumed that
final and complete information is received on deaths, serious adverse
events, and adverse events that caused discontinuation for all of these
additional studies by *.
It is assumed that Alteon will be responsible for preparing all text
for the NDA, other than the Statistical Methodology section, ISE, ISS,
remainder of the Clinical Section, the Clinical Data Summary, the
Risk-Benefit section, the Action I study report, and the Action II
abbreviated study report.
Quintiles has also included as an option, costs for the 120 day Safety
Update. This assumes that there will be 40-45 tables, and 100-120 pages
of text (at 1.5 line spacing). Costs have been included for one (1)
draft version after which Quintiles will incorporate Alteon's comments
to produce the final version. The costs assume that the tables will be
based only on data from Action I compassionate use and AE updates to
Action I data in the NDA if needed. Any additional data for the ESRD
study will be discussed in the text only.
NDA COMPILATION AND SUBMISSION
Quintiles has estimated the NDA to be 90 volumes. Labor costs
associated with the compilation of six (6) copies of the application
have been included in the budget. Labor costs for each additional copy
over six (6) is estimated at $* per copy.
For every volume over 90, an additional cost of $* per volume will be
added. Any changes to a paginated volume requested by Alteon will also
incur an additional cost
* Confidential Treatment Requested
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of $* per volume.
The estimated cost for the hand delivery of the application to the FDA
is $*. This cost has been included in the budget. If Alteon desires to
use Federal Express in lieu of hand delivery, the estimated cost would
be approximately $*. These estimates are based on the delivery of 180
volumes to the FDA (2 copies of a 90 volume submission). Actual
delivery or shipping costs for the final NDA submission will be
invoiced to Alteon at cost.
The estimated cost for shipping the NDA to Alteon via Federal Express
is $* per copy. The budget includes the shipping of 4 copies to Alteon
(one master and three copies).
PROJECT MANAGEMENT
Quintiles has included an estimated cost for providing Alteon with
study progress reports, as needed.
Cost estimates include six client meetings with Alteon (at Alteon) have
been included in the budget. It is estimated that six project team
members from Quintiles will attend the face-to-face client meetings.
Costs have also been included for weekly teleconferences between Alteon
and Quintiles in the budget. It is estimated that eight project team
members from Quintiles will participate in these weekly
teleconferences.
* Confidential Treatment Requested
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ATTACHMENT B
REVISED PAYMENT SCHEDULES
24
AMENDMENT TO CLINICAL SERVICES AGREEMENT
ATTACHMENT B: SUMMARY PAYMENT SCHEDULE
Protocols AGPF0002 and AGPF0009, Drug Safety Monitoring and NDA
*
* Confidential Treatment Requested
Page 1
25
AMENDMENT TO CLINICAL SERVICES AGREEMENT
ATTACHMENT B: PROJECT PAYMENT SCHEDULE
002 and AGPF0009
*
Safety Monitoring
*
NDA
*
* Confidential Treatment Requested
Page 2
26
ATTACHMENT C
SCOPE OF WORK AMENDMENT
27
AMENDMENT TO CLINICAL SERVICES AGREEMENT
ATTACHMENT C
REVISED SCOPE OF WORK
FOR
NEW DRUG APPLICATION SERVICES
AND
ACTION I & ACTION II FINAL STUDY REPORTS
Prepared for:
Alteon, Inc.
Submitted by:
Quintiles, Inc.
Research Triangle Park, North Carolina
July 1, 1998
28
TABLE OF CONTENTS
1.0 Executive Summary ...............................................1
2.0 Services Checklist ..............................................2
3.0 Project Timeline for Tasks Involving Action I ...................4
4.0 Project Timeline for Tasks Involving Action II Alone ............7
5.0 Scope of Work ...................................................8
6.0 Budget .........................................................15
7.0 Budget Notes ...................................................17
Appendix 1: Proposed List of Tables for the Alteon Integrated Summary of
Safety
Appendix 2: Proposed List of Tables and Figures for the Alteon Integrated
Summary of Efficacy, together with a Proposed List of the
Corresponding Tables and Figures in Action I and Action II
Study Reports
29
1.0 EXECUTIVE SUMMARY
The enclosed documents are a revised scope of work and timeline for the
IDDM Pimagedine NDA submission. The scope of work and timeline has been
revised to reflect the additional tasks requested at the April 16, 1998
meeting between Alteon and Quintiles.
1
30
2.0 SERVICES CHECKLIST
----------------------------------------------------------------------------------- --------------- ----------------
ACTIVITY ALTEON QUINTILES
----------------------------------------------------------------------------------- --------------- ----------------
PROJECT MANAGEMENT X X
----------------------------------------------------------------------------------- --------------- ----------------
DATA MANAGEMENT
----------------------------------------------------------------------------------- --------------- ----------------
Last Patient Visit (Action I Study) X X
----------------------------------------------------------------------------------- --------------- ----------------
Last Patient Visit (Action II Study) X X
----------------------------------------------------------------------------------- --------------- ----------------
Database Lock (Action I Study) X
----------------------------------------------------------------------------------- --------------- ----------------
Database Lock (Action II Study) X
----------------------------------------------------------------------------------- --------------- ----------------
Preparation For Data Review Meetings For Action I & Action II Study X
----------------------------------------------------------------------------------- --------------- ----------------
BIOSTATISTICAL OPERATIONS
----------------------------------------------------------------------------------- --------------- ----------------
Develop Annotated Report Outline (ARO) and Table Shells for Integrated Summary of X
Safety (ISS)
----------------------------------------------------------------------------------- --------------- ----------------
Develop ARO and Table Shells for Integrated Summary of Efficacy (ISE) X
----------------------------------------------------------------------------------- --------------- ----------------
Develop ARO for Action I study X
----------------------------------------------------------------------------------- --------------- ----------------
Develop ARO for Action II study X
----------------------------------------------------------------------------------- --------------- ----------------
Pre-NDA Meeting Planning/Attendance X X
----------------------------------------------------------------------------------- --------------- ----------------
Preparation for Data Review Meetings for Action I and Action II studies X
----------------------------------------------------------------------------------- --------------- ----------------
Prepare text for Statistical Methodology Section covering analyses for tables X
produced by Quintiles in the ISS or ISE
----------------------------------------------------------------------------------- --------------- ----------------
Integration of Action I and Action II ISS Databases (IDB) X
----------------------------------------------------------------------------------- --------------- ----------------
Statistical Analyses and Tables for the Action I study report X
----------------------------------------------------------------------------------- --------------- ----------------
Statistical Analyses and Tables for the Action II study report X
----------------------------------------------------------------------------------- --------------- ----------------
Statistical Analysis and Tables for ISE from Action I study only (a subset of
the X tables produced for the Action I study report)
----------------------------------------------------------------------------------- --------------- ----------------
Statistical Analysis and Tables for ISS from Action I study, Action II study (a
X subset of the tables produced for the Action I and Action II study reports),
and from IDB
----------------------------------------------------------------------------------- --------------- ----------------
Produce Data Listings for Action I and Action II X
----------------------------------------------------------------------------------- --------------- ----------------
CRF Scanning and Indexing X
----------------------------------------------------------------------------------- --------------- ----------------
Produce CRF Tabulations for Action I and Action II Study (if no FDA waiver is X
obtained)
----------------------------------------------------------------------------------- --------------- ----------------
2
31
----------------------------------------------------------------------------------- --------------- ----------------
ACTIVITY ALTEON QUINTILES
----------------------------------------------------------------------------------- --------------- ----------------
Produce an abbreviated integrated clinical & statistical study report for Action X
II
----------------------------------------------------------------------------------- --------------- ----------------
Produce an integrated clinical & statistical study report for Action I X
----------------------------------------------------------------------------------- --------------- ----------------
Prepare ISE Text X
----------------------------------------------------------------------------------- --------------- ----------------
CLINICAL SCIENCES
----------------------------------------------------------------------------------- --------------- ----------------
Develop ARO and Table Shells for ISS X
----------------------------------------------------------------------------------- --------------- ----------------
Develop ARO and Table Shells for ISE X
----------------------------------------------------------------------------------- --------------- ----------------
Develop ARO for Action I study X
----------------------------------------------------------------------------------- --------------- ----------------
Develop ARO for Action II study X
----------------------------------------------------------------------------------- --------------- ----------------
Pre-NDA Meeting Planning/Attendance X X
----------------------------------------------------------------------------------- --------------- ----------------
Produce an abbreviated integrated clinical & statistical study report for Action X
II
----------------------------------------------------------------------------------- --------------- ----------------
Produce an integrated clinical & statistical study report for Action I X
----------------------------------------------------------------------------------- --------------- ----------------
Prepare ISE Text X
----------------------------------------------------------------------------------- --------------- ----------------
Prepare ISS Text X
----------------------------------------------------------------------------------- --------------- ----------------
Prepare remaining parts of Clinical Section X
----------------------------------------------------------------------------------- --------------- ----------------
Prepare Clinical Data Summary (Item 3) X
----------------------------------------------------------------------------------- --------------- ----------------
Prepare draft Risk-Benefit Section X
----------------------------------------------------------------------------------- --------------- ----------------
REGULATORY OPERATIONS
----------------------------------------------------------------------------------- --------------- ----------------
Regulatory Consulting X
----------------------------------------------------------------------------------- --------------- ----------------
NDA Compilation X
----------------------------------------------------------------------------------- --------------- ----------------
3
32
3.0 PROJECT TIMELINE FOR TASKS INVOLVING ACTION I
MILESTONE
Draft ISS ARO and Draft ISE ARO to Alteon *
Contract Signature *
Alteon's Comments on Draft ISS &
ISE AROs Received *
Final ISS & ISE AROs Developed *
Alteon's Comments received on
Final ISS & ISE AROs *
Draft Action I ARO to Alteon *
Alteon's Draft Action I ARO
Comments To Quintiles *
Last Patient completes Action I study *
Final Action I ARO To Alteon *
Action I Data Review Meeting *
Data Review Updates Complete for
Action I study *
Locked Database for Action I study *
Key Draft ISS Tables for Action I
Available *
Last Draft ISS Tables for Action I
Available (from Appendix 1 of the
March 18, 1998 proposal) *
Integrated Database (IDB) Lock *
Last Draft Additional ISS Tables for
Action I Available *
Last Draft Action I ISE Tables Available *
Last Draft ISS Tables Available from
Integrated Database for Action I & II *
* Confidential Treatment Requested
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MILESTONE
Alteon Review of ISS Tables (for Action I alone) Complete *
Alteon Review of Action I ISE Tables Complete *
Alteon Review Complete for ISS Tables
Based on IDB *
Final ISS Tables (for Action I alone) Available *
Final Action I ISE Tables Available *
Final Draft ISS Tables Available from IDB *
Draft Action I Study Report Complete (already QC-ed
and Expert Reviewed) *
Alteon Review of First Draft of Action I Study
Report Complete *
Three Day Roundtable on Action I
Study Report Completed *
Draft ISE Text Complete (already QC-ed
and Expert Reviewed) *
Final Action I Study Report Complete(already QC-ed
and Expert Reviewed) *
Alteon review of First Draft of ISE Text Complete *
One Day Roundtable on ISE Text *
Draft ISS Text Complete (already QC-ed
and Expert Reviewed) *
Alteon review of First Draft of ISS Text Complete *
* Confidential Treatment Requested
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MILESTONE
Final ISE Text Complete (already QC-ed
and Expert Reviewed) *
Final NDA Items to Quintiles for Compilation
(Except Risk-Benefit Section & Introduction
to Section 8) *
Two Day Roundtable on ISS Text Complete *
CRF Tabulations for Action I Complete *
Draft Clinical Data Summary & Quintiles' part
of Application Summary both Complete *
Final ISS Text Complete (already QC-ed
and Expert Reviewed) *
Draft Risk-Benefit Section Complete *
Alteon's review of Draft Clinical Data
Summary & Application Summary Complete *
Alteon Finalization of Risk Benefit Section Complete *
Draft Introduction to Section 8 (Clinical
Section) Complete *
Alteon Review of Introduction to Clinical
Section Complete *
Final Introduction to Clinical Section Complete. *
Final Clinical Data Summary & Quintiles' part of
Application Summary both Complete *
NDA Submitted to FDA *
* Confidential Treatment Requested
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35
Note: This timeline is as Proposal 4, but with the following
changes/assumptions:
1. Alteon review of last batch of draft tables for Action I, ISE, and ISS
is completed within * days of these tables being produced.
2. There are 2 drafts of the Action II report, but only 1 draft of the
Action I report, the ISS, and the ISE.
3. Safety text from Action II study is suitable for inclusion in the ISS
without change and no additional text on safety data from Action II is
needed for the ISS. Safety text from Action I study is suitable for
inclusion in the ISS without change and no additional text on safety
data from Action I is needed for the ISS (other than for Action I data
integrated with Action II data).
4. Efficacy text from Action I study is suitable for inclusion in the ISE
without change and no additional text on efficacy data from Action I is
needed for the ISE.
5. Roundtables scheduled for Action I text, the ISE, and the ISS to take
place in RTP. Prior to the start of each session integrated written
comments (including comments from Alteon, Genentech, and any other 3rd
parties) are to be supplied to Quintiles. During these sessions text to
be modified online as far as possible, but by the end of each session
all further changes are to have been clearly identified.
6. It is assumed that no changes are needed to the text (for Action I
study report, the ISE, or the ISS) after Quintiles delivers the second
(final) version to Alteon.
7. Alteon is available at RTP to provide early input to the remaining
documents (Clinical Data Summary, part of the Application Summary, and
the Risk-Benefit Section).
8. Dates are now included for Action I and Action II AROs.
* Confidential Treatment Requested
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4.0 PROJECT TIMELINE FOR TASKS INVOLVING ACTION II ALONE
Milestone
Last Patient completes Action II study *
Draft Action II ARO To Alteon *
Alteon's Draft Action II ARO Comments to Quintiles *
Final Action II ARO to Alteon *
Action II Data Review Meeting *
Data Review Updates Complete for Action II study *
Locked Database for Action II study *
Last Action II ISS Tables Available *
Last Action II ISE Tables Available *
Alteon Review of Action II Tables Complete *
Final Action II Tables Complete *
First Draft of Action II Abbreviated Report Complete *
Alteon Review of First Draft of Action II Text Complete *
Second Draft of Action II Abbreviated Report Complete *
Alteon Review of Second Draft of Action II Text Complete *
Final Action II Abbreviated Report Complete *
CRF Tabulations for Action II Complete *
* Confidential Treatment Requested
8
37
5.0 SCOPE OF WORK
PROJECT MANAGEMENT
1. Quintiles will assign a Project Manager to serve as Alteon's
primary contact within Quintiles. The Project Manager is
responsible for maintaining the flow of project information to
Alteon and the Quintiles Project Team. The Project Manager
will:
o Maintain regular contact with Alteon concerning
project issues and timelines
o Conduct team meetings weekly or as needed and
generate and distribute minutes of team meetings
o Coordinate and attend the meetings for follow-up on
action items, and implementation of resolutions
o Forward reports to Alteon monthly, or as needed, and
provide internal status reports to senior Quintiles
staff
o Coordinate communications within the entire Project
Team
o Track the budget and report, clarify, and justify
budgetary issues Prepare assessment of task
completion reports. Review monthly Work in Progress
(WIP) reports. Review monthly Budget vs. Actual
reports by tasks. Prepare monthly variance analysis
and projection of overall cost to complete
o Generate and monitor timelines on a monthly, or as
needed, basis
o Monitor task completion and report to the Contracts
Manager any modifications or significant events that
could affect the administration of the contract
o Give day-to-day direction to the Quintiles Project
Team and communicate goals, deadlines, and strategy
to team members
o Ensure that ICH guidelines are adhered to for every
task associated with the NDA submission
o Provide regular updates to Alteon on the progress of
the project, including issues, and proposed
resolutions
9
38
BIOSTATISTICAL AND CLINICAL SCIENCES SERVICES
2. Quintiles' Biostatistical Operations and Clinical Sciences Project Team
members will provide the following services:
a. Prepare an Annotated Report Outline (ARO) for the Integrated
Summary of Safety (ISS) prior to the Pre-NDA meeting and
subsequently produce table shells (Clinical Sciences and
Biostatistics)
b. Prepare an ARO for the Integrated Summary of Efficacy (ISE)
prior to the Pre-NDA meeting and subsequently produce table
shells (Biostatistics and Clinical Sciences)
c. Prepare an ARO for the Action I study (Biostatistics and
Clinical Sciences)
d. Prepare an ARO for the Action II study (Biostatistics and
Clinical Sciences)
e. Integrate the Action I and Action II ISS Databases for the
purpose of analyzing and producing tables for the Integrated
Summaries of Safety (Programming, Biostatistics, and QC)
f. Generate the final analyses for the Action I study report
(Biostatistics, Programming, and QC)
g. Generate the final analyses for the Action II study report
(Biostatistics, Programming, and QC)
h. Generate the final analyses for the ISS tables from the Action
I study, the Action II study (a subset of the tables produced
for the Action I and Action II study reports), and in cases
where Action I and Action II data is combined (Biostatistics,
Programming, and QC)
i. Generate the final analyses for the ISE tables from the Action
I study only, which will be a subset of the analyses in the
Action I study report (Biostatistics, Programming, and QC)
j. Write the statistical methods section of the NDA covering
analyses for Tables produced by Quintiles in the ISS or ISE
(Biostatistics and QC)
k. Prepare for and participate in the Data Review Meetings for
the Action I and Action II studies (Biostatistics,
Programming, and QC)
10
39
1. Generate the final data listings for the Action I and Action
II studies (Programming, Biostatistics, and QC)
m. Generate the CRF Tabulations for the Action I and Action II
studies (Programming, Biostatistics, and QC) if no FDA waiver
is obtained
n. Produce an abbreviated integrated clinical and statistical
report for the Action II study (Biostatistics, Clinical
Sciences, and QC)
o. Produce an integrated clinical and statistical report for the
Action I study (Biostatistics, Clinical Sciences, and QC)
p. Prepare ISE text (Clinical Sciences, Biostatistics, and QC)
q. Prepare ISS text (Clinical Sciences, Biostatistics, and QC)
r. Prepare remaining parts of the Clinical Section (Clinical
Sciences and QC)
s. Prepare Clinical Data Summary (Clinical Sciences and QC)
t. Prepare draft Risk-Benefit section (Clinical Sciences and QC)
3. Data Review Meetings will be held with Alteon for Action I and Action
II prior to database lock for each study.
4. Quintiles will develop AROs for the ISS, the ISE, the Action I study
report, and the Action II abbreviated study report. Two (2) draft
versions of the ISS and ISE AROs and one (1) draft version of the AROs
for the study reports will be submitted to Alteon. Quintiles will
incorporate Alteon's comments after each draft.
5. Quintiles will provide Alteon with two (2) draft versions of each of
the following: ISS table shells, ISE table shells, and additional table
shells needed for the Action I or Action II study reports (excluding
those produced by third parties). Quintiles will incorporate Alteon's
comments after each draft.
6. Quintiles will integrate the adverse events, laboratory data, and ▇▇▇▇▇
▇▇▇▇▇ data from the Action I and Action Il studies to form an
integrated database for safety. Partial integration (as needed for the
interaction analyses in the ISE and/or ISS) will be carried out for
demographics, medications, and medical history. No integration is
planned for ECGs, efficacy, or any other data.
11
40
7. Quintiles will generate 399 tables (141 for Action I alone, a further
149 for Action II above, and a further 109 for Action I and Action II
combined), including 64 unique tables, and 20 figures for the ISS. A
full list of the ISS tables which Quintiles has assumed will be
required is provided in Appendix 1.
8. Quintiles will generate 85 tables (including 35 unique tables), and 24
figures for the ISE, all of which will be based on Action I alone. A
full list of the ISE tables which Quintiles has assumed will be
required, is provided in Appendix 2.
9. Quintiles will produce 25 data listings for the Action I study report
and 25 data listings for the Action II study report. After receipt of
one integrated set of comments from Alteon, the corresponding final
data listings will be produced in each case.
10. Quintiles will produce 215 tables for the Action I study report, 86
unique tables, and 33 figures. A total of 211 of these tables and all
figures will be identical (other than header information) to a
corresponding ISS or ISE table. A full list of the Action I tables
which Quintiles has assumed will be required is provided in Appendices
I and 2.
11. Quintiles will produce 230 tables for the Action II abbreviated study
report, 88 unique tables, and 32 figures. A total of 153 of these
tables and 11 figures will be identical (other than header information)
to a corresponding ISS table. A full list of the Action II tables which
Quintiles has assumed will be required is provided in Appendices 1 and
2.
12. Quintiles will produce CRF tabulations for the Action I and Action II
studies unless a waiver is provided by the FDA. After receipt of one
integrated set of comments from Alteon, the final CRF Tabulations will
be produced in each case.
13. Quintiles will provide Alteon with one (1) draft version of the
Statistical Methodology Section of the NDA, including details on all
statistical methodology used in the analyses carried out by Quintiles
for the ISS and ISE tables. After receipt of one integrated set of
comments from Alteon, the final version will be produced incorporating
these comments.
14. Quintiles estimates that the key draft ISS tables based on Action I
will be submitted to Alteon for review * weeks after Action I database
lock. The remaining draft ISS tables based on Action 1, except for the
AE prevalence tables, will be delivered in two further batches within *
weeks after Action I database lock. The AE prevalence tables will be
produced within * weeks of Action I database lock. Quintiles estimates
that the ISS tables based on Action
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II alone will be produced in 3 batches with the first delivered * weeks
after Action II database lock, and the last delivered within * weeks of
Action II database lock. Quintiles estimates that those ISS tables
based on data combined from Action I and Action II will be submitted to
Alteon for review within * weeks of database lock for the integrated
database. In all cases one draft version of the tables will be
produced, and one final version will be produced that incorporates
Alteon's comments on the draft tables.
15. Quintiles estimates that the last draft ISE tables based on Action I
will be delivered within * weeks after Action I database lock (subject
to the set of assumptions given in Section 5 of this proposal). Some
ISE tables will be delivered in batches prior to this date. In all
cases one draft version of the tables will be produced, and one final
version will be produced that incorporates Alteon's comments on the
draft tables.
16. Quintiles estimates that those additional safety tables needed for the
Action I or Action II study reports (as specified in Appendix 1) will
be produced according to the timeline (relative to the individual
study's database lock) described in #14. Likewise Quintiles estimates
that any additional efficacy or other non-safety tables needed for the
Action I or Action 11 study reports (as specified in Appendix 2) will
be produced according to the timeline (relative to the individual
study's database lock) described in # 15.
17. Quintiles will provide Alteon with two (2) draft versions of the Action
II study report text. For the Action I study report text, the ISE text,
the ISS text, text for the remainder of the Clinical Section, and text
for the Clinical Data Summary (Item 3) Quintiles will provide one (1)
draft version. For the Risk-Benefit section Quintiles has assumed that
Alteon will finalize this document after Quintiles produces the first
draft. Roundtable discussion will be held to discuss comments on Action
I study report, ISE, Text, ISS Text. Quintiles will incorporate
comments from roundtable discussions and submit final version to
Alteon.
18. Quintiles will provide ten days of biostatistical consultation
services. Any additional biostatistical consultation will be charged to
Alteon on a fee-for-service basis.
19. Quintiles will provide two (2) attendees (one from Clinical Sciences
and one from Biostatistics) at the Pre-NDA meeting. Any additional
attendees will be billed to Alteon on a fee-for-service basis.
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REGULATORY SERVICES-NDA COMPILATION AND SUBMISSION
20. Quintiles will format this NDA submission according to
specifications reviewed and approved by Alteon and meeting
current FDA guidelines. Quintiles' responsibilities will
include the overall duplication and assembly of the NDA.
This process consists of developing a table of contents and
a cross-referencing index, formatting, organizing, labeling,
paginating, duplicating, and assembling each volume.
21. Quintiles will paginate each volume of the application and
prepare a table of contents for each section. Quintiles will
perform quality assurance activities on the master copy to
assure completeness and accuracy. Quintiles will visually
inspect each page of all photocopied documents for clarity
and completeness, ensuring all pages are present and
correct.
22. The submission will follow NDA guidelines. Quintiles will
provide the master document and six (6) copies; one (1)
archival copy to FDA, one (1) review copy to FDA, three (3)
copies (and the master document to Alteon), and one (1) copy
retained by Quintiles. Checklists will be used to assure
completeness of the NDA technical sections. Quintiles will
archive its copy of the NDA for three (3) years.
23. Upon five (5) days verbal or written notice to Quintiles,
Alteon may conduct quality assurance audits of Quintiles'
operations at Quintiles at mutually agreed upon times. The
audits will include, but not be limited to, procedures for
the processing and quality assurance (QA) of the NDA
compilation. Alteon will make every effort to avoid
interfering with the routine of Quintiles' personnel during
these audits.
24. Alteon will make a final inspection of the application no
later than * weeks prior to submission to FDA. If some NDA
volumes are not compiled for submission within this time
because they arrive at Quintiles at a date later than *
weeks before submission date, Alteon will not review the
finalized volumes before submission. Any shortcomings or
revisions needed because of Quintiles' error will be
corrected by Quintiles at no cost to Alteon. Any new
additions or revisions requested by Alteon at this time will
be made at Quintiles' standard rates and may delay the
submission.
25. Quintiles will make arrangements for packing the NDA with
each carton identifying the box number, Alteon, the volume
numbers, and whether the carton contents contains archival
or review copies. Quintiles will make arrangements for
shipment of two (2) copies of the application to the FDA,
and the master and three (3) copies to Alteon.
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26. Quintiles will assume responsibility for FDA refusal-to-file
due to problems in format, legibility and ease to review.
Quintiles will not assume responsibility for FDA
refusal-to-file due to lack of sufficient data to support
the safety and effectiveness of Pimagedine.
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6.0 BUDGET
The following budget is based on the assumptions, tasks, and delivery
schedules detailed in this proposal. Should the scope of the project
change or additional services be requested, a revised budget will be
submitted for Alteon's approval prior to the initiation of these
services. This quotation is valid for 90 days.
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ALTEON, INC.
ESTIMATED NDA BUDGET for 11 MONTHS
NDA Preparation
o Table of Contents *
o Application Summary (Clinical Section only) *
o CMC *
o Labeling *
o Non-Clinical Pharmacology and Toxicology *
o Human PK and Bioavailability and
Clinical Pharmacology *
o Microbiology *
o Overall Clinical Summary *
o Clinical Pharmacology *
o Individual Study Reports
Action I Study Report *
Action II Study Report *
o Patent Narratives *
o Integrated Summary of Safety (Integrated
database creation, Analyses and Tables) *
o Integrated Summary of Efficacy (Analysis and Tables) *
o Integrated Summary of Benefits & Risks *
o Safety Update Report (See Optional Costs
category on next page) *
o Statistical Methods Section (ISS Methods Insert) *
o CRF Tabulations (See Optional Costs
category on next page) *
o Case Report Forms *
o Patent Information and Certification *
o NDA Compilation & Cross Referencing *
o Project Management (includes Administrative Support) *
o Clinical Pharmacology Support *
Sub-Total NDA Preparation *
CONTINUED ON NEXT PAGE
OTHER SERVICES
o NDA Strategy/Pre-NDA Meeting *
o Other Services:
Expert Consulting-Biostatistics, Clinical
Sciences and Regulatory Services *
Face to Face Client Meetings (6 meetings;
6 attendees at each) *
Teleconference Client Meetings (Weekly;
8 attendees at each) *
Project Startup and Planning *
SUB-TOTAL OTHER SERVICES *
TOTAL SERVICES *
MISCELLANEOUS COSTS
o Travel
Client Meetings *
6 meetings at Alteon; 6 attendees at each
meeting
Pre-NDA Meeting *
o Telephone, Supplies, and Computer Support *
o Shipping of NDA Volumes
Hand Delivery of NDA to FDA (based on
2 copies of 90 volume submission) *
Federal Express Delivery of remaining
4 copies of 90 volume application to
Alteon *
Sub-Total Miscellaneous Costs *
TOTAL NDA BUDGET COST *
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OPTIONAL COSTS (Not Included in Total Budget Costs)
o Safety Update Report *
o CRF Tabulations *
o Action II efficacy tables and text in ISE *
Subtotal Optional Costs *
Total Costs Including Optional Costs *
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7.0 BUDGET NOTES
Quintiles' scope of work for the NDA Preparation for Pimagedine includes
Regulatory Affairs Consulting, Clinical Sciences, Biostatistics, Programming,
QC, and Project Management services. Assumptions are based on discussions
between Quintiles and Alteon. Deviations in these assumptions may require a
modification to the budget and/or timelines.
GENERAL NOTES
Quintiles' participation in this project is based on * consecutive months
beginning *. Should the time line increase/decrease, the budget will be adjusted
accordingly.
The budget is based on Quintiles' 1998 daily rates. If the Services hereunder
last longer than one (1) year, Quintiles' costs may be increased at the
beginning of each year, commencing one year after the date the Agreement is
executed, to reflect increases or decreases in Quintiles' costs on a prospective
basis only. Quintiles' costs may be increased or decreased for the next twelve
(12) month period using the percentage change in the wages/earnings survey as
published in The Economist for the applicable currencies over the preceding
twelve (12) month period.
Any costs associated with audits performed by Alteon at Quintiles' facilities
will be invoiced to Alteon at cost.
BIOSTATISTICAL AND CLINICAL SCIENCES SERVICES
Costs for error resolution for the following data to be received from external
vendors have not been included in the budget: Covance laboratory data, Scripps
Labs' data, Fundus photography data (University of Wisconsin, Madison), GFR data
(from Covance), the Quality of Life data (from ▇▇▇▇▇▇ Associates), and plasma
pimagedine data (from Alteon).
Quintiles has assumed that a final transfer of all data from each vendor will be
received as locked databases no later than * for the Action I study and no later
than * for the Action II study. Quintiles assumes that at least 2 interim
transfers of each of these databases will be received (at approximately * months
prior to the last patient visit and at * months prior to the last patient visit
for the Action I study and at approximately * weeks and * weeks prior to the
last patient visit for the Action II study). Quintiles will carry out checks
prior to database lock to determine and seek error resolution for any systematic
problems or inconsistencies found in each of these
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databases. However, it is assumed that final responsibility for locking each
vendor database will reside with each individual vendor. Any additional costs
incurred by Quintiles as a result of errors or inconsistencies in any of the
databases delivered to Quintiles as a locked database will be billed on a
fee-for-service basis. This will include costs for re-running analysis files or
tables.
Quintiles has assumed that no changes to the definition of the Per Protocol
population will take place after database lock. Any costs (due to re-programming
analysis files and re-running tables) as a result of changes to the definition
of the Per Protocol population after database lock will be billed on a
fee-for-service basis.
Quintiles has assumed that adverse events of special interest (including the
exact definition of flu syndrome) for the NDA will have been defined (or the
rule for selecting them has been defined) by *. Any costs (due to re-programming
analysis files and re-running tables) as a result of changes to the definition
of special interest adverse events after * will be billed on a fee-for-service
basis.
Quintiles has budgeted for a data review meeting for the Action I study and a
data review meeting for the Action II study with an anticipated date of *
working days prior to database lock in each case. For these meetings Quintiles
will provide data dumps (SAS Proc Prints of raw data) for all CRF data only. In
addition, frequencies (for binary data), and the highest and lowest values as
well as quantiles (for continuous data) will be provided for CRF data on the
following variables: key disposition variables, demographics, the primary
efficacy parameter, adverse events, and key laboratory parameters (including
those which are key secondary parameters). Any outstanding discrepant dates or
other questionable or missing information related to the primary efficacy
parameter will be fully summarized. It is assumed that no new DCFs will be
issued as a result of discussions at the data review meetings, as otherwise
delays are likely to result for all subsequent deliverables.
Costs to develop the Integrated Summary of Safety (ISS) Annotated Report Outline
(ARO), Integrated Summary of Efficacy (ISE) ARO, Action I ARO, Action II ARO,
ISS Table Shells, ISE Table Shells, ISS Tables, ISE Tables, Data Listings for
Action I and Action II, CRF Tabulations for Action I and Action II (if no FDA
waiver is given), text for the Action I integrated clinical and statistical
study report, text for the Action II abbreviated integrated clinical and
statistical study report, ISE text, ISS text, text for the remainder of the
Clinical Section, text for the Clinical Data Summary, text for the Risk-Benefit
section, and text for the Statistical Methodology section of the NDA have all
been included in the budget. Those tables to be included in the ISS, the ISE,
the Action I study report, and the Action II abbreviated study report are
specified in Appendices 1 and 2. Estimated costs include one round of review and
incorporation of consolidated comments from Alteon to create the final version
for all Tables, Data Listings, CRF Tabulations, Action I ARO, Action II ARO,
text for the Action I study
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report, ISE text, ISS text, text for the remainder of the Clinical Section, text
for the Clinical Data Summary, and Statistical Methodology text. Estimated costs
for the ISS ARO, the ISE ARO, Table Shells, and text for the Action II
abbreviated study report, allow for two rounds of review and incorporation of
comments. In all cases it is assumed that Alteon provides one integrated set of
comments (including comments from ▇▇▇▇▇▇ ▇▇▇▇▇▇▇▇▇▇ University and any other
third parties). For the Risk-Benefit section costs assume that Quintiles will
produce one draft version after which Alteon will finalize the document.
It is assumed that the final SAE documentation (SAE reporting and source
documentation) is received from all investigator sites by * for the Action I
study and * for the Action II study.
Any additional tables, figures, or listings Alteon requires outside of the
approved AROs for the ISS, the ISE, the Action I study, or the Action II study
will be discussed and any additional fees negotiated with Alteon.
All patient narratives will be prepared by Alteon. Should Alteon request that
Quintiles prepare patient narratives, Quintiles will provide Alteon a cost
estimate for development of patient narratives.
At Alteon's request, Quintiles will send printouts of the concomitant medication
and AE coding mappings on two occasions, once prior to Action II database lock
and once prior to Action I database lock. Quintiles has assumed that all
Quintiles and Alteon reconciliation between Quintiles' coding dictionaries and
the coding dictionaries used in other studies (including the ESRD study
conducted by ACER/EXCEL) will have taken place prior to Action II database lock.
Quintiles estimated dates for production of the ISE and ISS tables assume that
no changes to coding dictionaries occur after Action Il database lock for terms
that are present in Action II, and no changes occur after Action I database lock
for terms that are present in Action I. In addition, any costs (due to
re-running analysis files or tables) as a result of changes in coding after
database lock will be billed on a fee-for-service basis.
Costs for 10 days of expert consulting each from the Biostatistics, Clinical
Sciences and Regulatory departments have been included in the budget. Estimated
costs are based on daily rates of $* for Biostatistics; $* for Clinical Sciences
and $* for Regulatory. Any additional expert consultancy above 10 days from any
of these departments will be billed on a fee-for-service basis.
Costs have been included for two (2) Quintiles' attendees (one from Clinical
Sciences and one from Biostatistics) at the Pre-NDA meeting. Any additional
attendees at Alteon's request will be billed to Alteon on a fee-for-service
basis.
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Costs have been included for Quintiles' expert review of the text for the ISS,
the ISE, the Action I study report, the Action II abbreviated study report, the
remainder of the Clinical Section, the Clinical Data Summary, and the
Risk-Benefit section by Clinical Sciences, the Project Medical Officer (or
another M.D.), Regulatory, and Biostatistics. For the statistical methodology
section and all AROs costs have been included for expert reviews by
Biostatistics, Clinical Sciences, and Regulatory. For tables and table shells
costs include expert review by Biostatistics and Clinical Sciences. For data
listings and CRF tabulations (if required) costs include expert review by
Biostatistics. All expert reviews will be carried out prior to delivery of these
items to Alteon.
Costs are included for a QC review of all deliverables of AROs, table shells,
tables, data listings, CRF tabulations, and text. These QC reviews will have
taken place prior to delivery of the items to Alteon.
Quintiles will generate 399 tables (141 for Action I alone, a further 149 for
Action II alone, and a further 109 for Action I and Action II combined),
including 64 unique tables, and 20 figures for the ISS. A full list of the ISS
tables which Quintiles has assumed will be required is provided in Appendix 1.
Quintiles will generate 85 tables (including 35 unique tables), and 24 figures
for the ISE, all of which will be based on Action I alone. A full list of the
ISE tables which Quintiles has assumed will be required, is provided in Appendix
2.
Quintiles will produce 215 tables for the Action I study report, 86 unique
tables, and 33 figures. A total of 211 of these tables and all figures will be
identical (other than header information) to a corresponding ISS or ISE table. A
full list of the Action I tables which Quintiles has assumed will be required is
provided in Appendices 1 and 2.
Quintiles will produce 230 tables for the Action II abbreviated study report, 88
unique tables, and 32 figures. A total of 153 of these tables and 11 figures
will be identical (other than header information) to a corresponding ISS table.
A full list of the Action II tables which Quintiles has assumed will be required
is provided in Appendices 1 and 2.
Additional analyses outside of the lists of tables provided in Appendices 1 and
2 can be provided, on a fee-for-service basis. However, certain additional ISE
analyses (including any exploratory analyses, any reasonable case analysis, and
any additional figures) may take longer than 7 weeks after database lock.
It is assumed that a total of 25 data listings will be produced for the Action I
study and 25 data listings will be produced for the Action II study.
Quintiles would recommend that Alteon seek a waiver from the FDA for CRF
tabulation production. However, if Alteon does not receive a waiver, Quintiles
estimates that CRF
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tabulation production for Action I and Action II would cost approximately $*
altogether.
It is assumed that the statistical methodology section of the NDA will be at
most 60 pages of text (at 1.5 line spacing). Further, it is assumed to cover
only statistical methodology corresponding to analyses produced by Quintiles in
the ISS or ISE, together with analysis discussion in the text of the ISS or ISE
by Quintiles. These methods will be discussed in the stats trial methodology
section of the NDA based on the methods sections from the corresponding study
reports. It is assumed that statistical methodology for analysis of Quality of
Life and plasma pimagedine will be provided to Quintiles as drop-in sections.
Quintiles has assumed that no tables from any study other than Action I and
Action II will be required for the ISS and no tables from any study other than
Action I will be required for the ISE. If additional tables are required from
other studies in the ISS or ISE then these will be billed on a fee-for-service
basis. ISS or ISE tables produced from studies other than Action I and Action II
may take longer than those produced for Action I and II.
Costs include tasks required to produce the key draft ISS tables for Action I
within * weeks of Action I database lock and the remaining draft ISS tables
(except for AE prevalence tables) for Action I will be delivered in * batches at
weekly intervals over the following * weeks. Costs also include tasks required
to produce AE prevalence tables within a further * weeks. Those tables which
correspond to the "key" ISS text (as defined by Alteon) will be given highest
priority. However, exactly which tables will be included in each of the these *
batches is also dependent on data-driven issues.
Costs include tasks required to produce ISS tables based on Action II alone in 3
batches with the first delivered within * weeks of Action II database lock and
the last delivered within * weeks of database lock. Costs for production of the
integrated ISS database assume that adverse events, laboratory data, and ▇▇▇▇▇
▇▇▇▇▇ is the only safety data that is fully integrated, and that this is based
only on Action I and Action II. It is further assumed that the only data that is
partially integrated is that part of the demographics, medications, and medical
history needed for the interaction analyses in the ISS and the ISE. It is
assumed that ECGs, efficacy data, and all other data will not be integrated at
all. Quintiles estimates that those ISS tables based on the integrated database
will be submitted to Alteon within * weeks of the integrated database lock.
Costs for the ISE assume that the last draft table for Action I from the list
specified in Appendix 2 will be produced within * weeks after Action I database
lock (subject to the assumptions set out in this proposal). Some ISE tables will
be delivered in batches prior to this date, but exactly which tables will be
included in any particular batch is highly dependent on data-driven issues.
Those tables corresponding to the most
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important efficacy parameters will be given the highest priority. However, it is
anticipated that those analyses based on survival endpoints (including analysis
for the primary efficacy parameter) will be in a later batch as they are likely
to be most affected by (data-driven) special cases, which arise very shortly
before database lock.
Quintiles estimates that any additional safety tables needed for the Action I or
Action II study reports will be produced according to the timeline (relative to
the individual study's database lock) described above. Likewise Quintiles
estimates that any additional efficacy or other non-safety tables needed for the
Action I or Action II study reports will be produced according to the timeline
(relative to the individual study's database lock) described above.
For the ISE and for the Action II efficacy analyses Quintiles has assumed that
the programs written by ▇▇▇▇▇▇ ▇▇▇▇▇▇▇▇▇▇ University to produce the ESMC
analyses (except for any code that reveals information that would unblind a
patient) will be received electronically by *. Further, it is assumed that any
additional code covering information related to a patient's treatment
assignment, together with all results from interim analyses will be provided
electronically * after unblinding.
For the ISE, it is further assumed that agreement is reached between Quintiles,
▇▇▇▇▇▇ ▇▇▇▇▇▇▇▇▇▇ University, and Alteon by * for Action I and Action II on all
analyses and all data analysis rules to be used in the ISS/ISE, the Action I and
Action II study reports, and in the interim and final analyses to be carried out
by ▇▇▇▇▇▇ ▇▇▇▇▇▇▇▇▇▇ University for either study. If different analysis rules
are followed by ▇▇▇▇▇▇ ▇▇▇▇▇▇▇▇▇▇ University or Alteon compared with the rules
to be adopted by Quintiles in the ISE and the ISS, then additional costs will
result for the reconciliation of these results with the results produced by
Quintiles. This will be billed on a fee-for-service basis. Alteon will be
alerted to any differences in analysis rules prior to reconciliation.
It is assumed that Quintiles writes the Action I Integrated Clinical &
Statistical Study report. The results section is assumed to be based on the 215
tables specified in Appendices 1 and 2 (85 tables identical to Action I ISE
tables a further 126 tables identical to Action I ISS tables and 4 additional
tables). It is assumed that methods and results sections covering plasma
pimagedine data, (including relationship of plasma pimagedine to efficacy or
safety) and Quality of Life date will be written by their corresponding vendors
or will be written by Alteon, and it is assumed that these sections will be
supplied to Quintiles as drop-in sections and that these will use section
numbering as specified by Quintiles. Further, it is assumed that text covering
results for Quality of life and plasma pimagedine data for the ISE (and for the
ISS if appropriate) will be supplied as a drop-in section.
It is assumed that Quintiles writes the Action II abbreviated Integrated
Clinical &
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Statistical Study. The results section is assumed to be based on the 209 tables
specified in Appendices 1 and 2 (153 tables identical to Action II ISS tables,
and 77 additional tables). It is assumed that methods and results sections
covering plasma pimagedine data and Quality of Life will be written by their
corresponding vendors or will be written by, (including relationship of plasma
pimagedine to efficacy or safety) Alteon. It is assumed that these sections will
be supplied to Quintiles as drop-in sections and that these will use section
numbering as specified by Quintiles. Further, it is assumed that text covering
results for Quality of life and plasma pimagedine data for the ISE (and for the
ISS if appropriate) will be supplied as a drop-in section.
Quintiles has assumed that an integrated set of comments is received from Alteon
within * days of shipment of each batch of ISS or ISE tables. Further, Quintiles
has assumed that draft tables will be revised to produce final tables as
indicated by the integrated comments from Alteon, within at most * weeks of
receipt of comments, except for the last batch of ISE tables where revised
tables will be shipped within * of receiving comments. This timeline assumes
that as a result of Alteon's comments on each batch of ISS or ISE tables, no new
tables are required, no additions to tables are required, no changes are made to
any definitions, and no additional exploratory analyses are needed.
Quintiles has assumed that Alteon is able to obtain FDA agreement to the ISS
ARO, the ISE ARO, and the data analysis rules for the ISS and ISE by *.
Quintiles also assumes that no additional analyses are required as a result of
the Pre-NDA meeting scheduled for *. If such additional analyses are required
then these will be billed on a fee-for-service basis and this is likely to
impact on the NDA timeline.
Quintiles has assumed that all data on patients who are lost to follow-up
(including any additional data collected as a result of active searching for
these lost to follow-up patients) is received at Quintiles by * for Action I
patients and by * for Action II patients.
Quintiles has assumed that the last DCF for any data retrieved for lost to
follow-up patients is resolved by * for Action I patients and by * for Action II
patients. Any delays in receipt of this information may lead to delays in all
subsequent dates on the timeline.
This budget estimate does not include costs for Quintiles to scan CRFs. Any
support provided by Quintiles in connection with the scanning of CRFs have not
been included in the budget. If required, this support will be invoiced to
Alteon at a daily rate of $*.
In order to lock the database for Action II within * months of the last patient
visit it is assumed that all CRF pages are available be collected at the last
monitoring visit (estimated to be on *). Further, it is assumed that all DCFs
receive a
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resolution from the sites within *.
It is assumed that the Action II abbreviated study report will be at most 120
pages in length (from Introduction to Conclusions based on 1.5 spacing) with
25-30 panels (in-text tables). No cost for patient narratives has been included,
but if it is required for Quintiles to produce these then they will be charged
on a fee-for-service basis.
It is assumed that the Action I study report will be 150-160 pages in length
(from Introduction to Conclusions based on 1.5 spacing) with 30-40 panels
(in-text tables). No cost for patient narratives has been included, but if it is
required for Quintiles to produce these then they will be charged on a
fee-for-service basis.
Quintiles costs and timelines assume that for the ISE only Action I will be
summarized from tables included in the ISE itself. It is also assumed that the
only additional studies summarized in the ISE text will be Action II and the
Dyslipidemia study. Costs for the ISE assume that there will be 150-200 pages of
text (at 1.5 line spacing).
Quintiles has also given separate costs for including tables based on Action II
in the ISE. In this option, such tables would be a subset of the tables produced
for the Action II study report and would differ from study report only in header
information.
Quintiles costs and timelines assume that for the ISS only Action I and Action
II will be summarized from tables included in the ISS itself. It is also assumed
that the only additional studies summarized in the ISS text will be those
studies listed in Appendix 3. Costs for the ISS assume that there will be
250-300 pages of text (at 1.5 line spacing).
Costs and timelines for the ISE and ISS text writing assume that Quintiles is
not responsible for production of analyses, tables, or study report text for any
studies other than Action I or Action II. Further, it is assumed that for all
studies other than Action I and Action II a final and complete study report
together with a set of tables is provided to Quintiles by *. In addition it is
assumed that final and complete information is received on deaths, serious
adverse events, and adverse events that caused discontinuation for all of these
additional studies by *.
It is assumed that Alteon will be responsible for preparing all text for the
NDA, other than the Statistical Methodology section, ISE, ISS, remainder of the
Clinical Section, the Clinical Data Summary, the Risk-Benefit section, the
Action I study report, and the Action II abbreviated study report.
Quintiles has also included as an option, costs for the 120 day Safety Update.
This assumes that there will be 40-45 tables, and 100-120 pages of text (at 1.5
line spacing). Costs have been included for one (1) draft version after which
Quintiles will incorporate Alteon's comments to produce the final version. The
costs assume that the tables will be
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55
based only on data from Action I extension study and AE updates to Action I data
in the NDA if needed. Any additional data for the ESRD study will be discussed
in the text only.
NDA COMPILATION AND SUBMISSION
Quintiles has estimated the NDA to be 90 volumes. Labor costs associated with
the compilation of six (6) copies of the application have been included in the
budget. Labor costs for each additional copy over six (6) is estimated at $* per
copy.
For every volume over 90, an additional cost of $* per volume will be added. Any
changes to a paginated volume requested by Alteon will also incur an additional
cost of $* per volume. The estimated cost for the hand delivery of the
application to the FDA is $*. This cost has been included in the budget. If
Alteon desires to use Federal Express in lieu of hand delivery, the estimated
cost would be approximately $*. These estimates are based on the delivery of 180
volumes to the FDA (2 copies of a 90 volume submission). Actual delivery or
shipping costs for the final NDA submission will be invoiced to Alteon at cost.
The estimated cost for shipping the NDA to Alteon via Federal Express is $* per
copy. The budget includes the shipping of 4 copies to Alteon (one master and
three copies).
PROJECT MANAGEMENT
Quintiles has included an estimated cost for providing Alteon with study
progress reports, as needed.
Cost estimates include six client meetings with Alteon (at Alteon) have been
included in the budget. It is estimated that six project team members from
Quintiles will attend the face-to-face client meetings.
Costs have also been included for weekly teleconferences between Alteon and
Quintiles in the budget. It is estimated that eight project team members from
Quintiles will participate in these weekly teleconferences.
* Confidential Treatment Requested
26
56
APPENDIX 1: PROPOSED LIST OF TABLES FOR THE ALTEON INTEGRATED SUMMARY OF SAFETY
Table Numbering Conventions:
1. All tables have numbers of the form X.X.X.
2. The first level (1.X.X, 2.X.X, etc) represents the nature of the data,
e.g., Patient Descriptives, AEs, Labs, etc.
3. The second level (X.1, X.2, X.3) indicates whether the table is based
on the Action I data (X. 1), or the Action II data (X. 2), or the
integrated database (X.3).
4. The third level (X.X.1, X.X.2, etc) represents the table number within
this data type-study combination.
5. Missing table numbers in any column indicates that the corresponding
tables will not be produced for that data (Action I, Action II, or
IDB).
----------------------------------------------------------------------------------------------------------------------
Integrated Summary of Safety (ISS)
Title
------------------------------------------
Integrated
Action I Action II Database
----------------------------------------------------------------------------------------------------------------------
PATIENT DESCRIPTIVES
----------------------------------------------------------------------------------------------------------------------
Patient Disposition - Study completion and treatment cessation 1.1.0 1.2.0 1.3.0
information - Enrolled patients (including information on
discontinuations due to dialysis and/or transplantation)
----------------------------------------------------------------------------------------------------------------------
Listing of patients excluded from the ITT population 1.1.1 1.2.1
----------------------------------------------------------------------------------------------------------------------
Patient Disposition by Center - Number of Patients Enrolled, Evaluated, 1.1.2 1.2.2
Ceased Treatment, and Dropped Out at each Center
----------------------------------------------------------------------------------------------------------------------
Patient disposition by visit (This table will show the number of 1.1.3 1.2.3
patients on-treatment at the protocol correct dose, on-treatment at the
protocol incorrect dose, off-treatment, dropped out, and lost to follow-up
at each visit for each treatment)
----------------------------------------------------------------------------------------------------------------------
Number of Patients with Major Protocol Deviations 1.1.4 1.2.4
----------------------------------------------------------------------------------------------------------------------
Listing of Patients with Major Protocol Deviations 1.1.5 1.2.5
----------------------------------------------------------------------------------------------------------------------
COMPLIANCE AND EXPOSURE TO STUDY MEDICATION
----------------------------------------------------------------------------------------------------------------------
Appendix 1 - Page 1
57
APPENDIX 1: PROPOSED LIST OF TABLES FOR THE ALTEON INTEGRATED SUMMARY OF SAFETY
----------------------------------------------------------------------------------------------------------------------
Integrated Summary of Safety (ISS)
Title
------------------------------------------
Integrated
Action I Action II Database
----------------------------------------------------------------------------------------------------------------------
Total duration of exposure to study medication overall and by 6-month 2.1.0 2.2.0 2.3.0
intervals (not accounting for gaps in study medication administration)
----------------------------------------------------------------------------------------------------------------------
Duration of exposure to study medication overall and by 6-month 2.1.1 2.2.1
intervals (accounting for gaps in study medication administration)
----------------------------------------------------------------------------------------------------------------------
Dose Titration (Including information on the number of times the dose 2.1.2 2.2.2
was changed, number of times patient was taken off study medication,
overall and by reason)
----------------------------------------------------------------------------------------------------------------------
Study medication compliance (This table will show the number of patients 2.1.3 2.2.3
in each of the following categories - < 80% compliance, 80%-120%
compliance, and > 120% compliance)
----------------------------------------------------------------------------------------------------------------------
DEMOGRAPHICS, BACKGROUND CHARACTERISTICS, AND MEDICAL HISTORY
----------------------------------------------------------------------------------------------------------------------
Patient demographics (age, age category, sex, race, weight, weight 3.1.0 3.2.0 3.3.0
category, height, BMI)
----------------------------------------------------------------------------------------------------------------------
Background Characteristics (smoking, duration of diabetes, Baseline 3.1.1 3.2.1 3.3.1
HbA1c, Baseline serum creatinine, Baseline GFR, Baseline proteinuria,
Baseline 24-hour urine creatinine clearance, Systolic BP, Systolic BP
category, Diastolic BP, Diastolic BP category, Insulin type, Insulin
daily dose, Baseline Triglycerides, Baseline Total cholesterol, Baseline
HDL cholesterol, Baseline LDL cholesterol, Total cholesterol to HDL ratio,
and for Action II only - cardiovascular morbidity)
----------------------------------------------------------------------------------------------------------------------
Medical History (including body system categories and several groups of 3.1.2 3.2.2 3.3.2
parameters from Baseline ECG form)
----------------------------------------------------------------------------------------------------------------------
PRIOR AND CONCOMITANT MEDICATIONS
----------------------------------------------------------------------------------------------------------------------
Incidence of prior medications at baseline In Appendix Table A1.0 of study report
only
----------------------------------------------------------------------------------------------------------------------
Appendix 1 - Page 2
58
APPENDIX 1: PROPOSED LIST OF TABLES FOR THE ALTEON INTEGRATED SUMMARY OF SAFETY
----------------------------------------------------------------------------------------------------------------------
Integrated Summary of Safety (ISS)
Title
------------------------------------------
Integrated
Action I Action II Database
----------------------------------------------------------------------------------------------------------------------
Incidence of concomitant medications taken prior to randomization In Appendix Table A2.0 of study report
only
----------------------------------------------------------------------------------------------------------------------
Incidence of key concomitant medications taken during the double-blind 4.1.0 4.2.0 4.3.0
treatment period [ACE inhibitors, [beta symbol]-blockers, diuretics,
Calcium channel antagonists, insulin (overall and by type), each prohibited
medication + for Action II only: troglitazone, sulfonylureas, metformin,
[alpha symbol]-glucosidase inhibitors, lipid lowering agents]
----------------------------------------------------------------------------------------------------------------------
Incidence of concomitant medications taken during the double-blind A1.0 A1.1
treatment period
----------------------------------------------------------------------------------------------------------------------
ADVERSE EVENTS
----------------------------------------------------------------------------------------------------------------------
Overall Incidence of Treatment Emergent Adverse Events 5.1.0 5.2.0 5.3.0
----------------------------------------------------------------------------------------------------------------------
Prevalence of Adverse Events in first 12 weeks by 2 week intervals 5.1.1 5.2.1 5.3.1
----------------------------------------------------------------------------------------------------------------------
Prevalence of Adverse Events by 3-month intervals 5.1.2 5.2.2 5.3.2
----------------------------------------------------------------------------------------------------------------------
Incidence of Treatment Emergent Adverse 5.1.3 5.2.3 5.3.3
Events in first 12 weeks by 2 week intervals (based on
treatment-emergence relative to the start of the interval)
----------------------------------------------------------------------------------------------------------------------
Incidence of Treatment Emergent Adverse Events by 3-month intervals 5.1.4 5.2.4 5.3.4
(based on treatment-emergence relative to the start of the interval)
----------------------------------------------------------------------------------------------------------------------
Cumulative Incidence of Treatment Emergent Adverse Events in first 12 5.1.5 5.2.5 5.3.5
weeks by 2 week intervals (based on treatment-emergence relative to the
time of randomization)
----------------------------------------------------------------------------------------------------------------------
Cumulative Incidence of Treatment Emergent Adverse Events by 3 month 5.1.6 5.2.6 5.3.6
intervals (based on treatment-emergence relative to the time of
randomization)
----------------------------------------------------------------------------------------------------------------------
Overall Incidence of Treatment Emergent Adverse Events by Severity 5.1.7 5.2.7 5.3.7
----------------------------------------------------------------------------------------------------------------------
Appendix 1 - Page 3
59
APPENDIX 1: PROPOSED LIST OF TABLES FOR THE ALTEON INTEGRATED SUMMARY OF SAFETY
----------------------------------------------------------------------------------------------------------------------
Integrated Summary of Safety (ISS)
Title
------------------------------------------
Integrated
Action I Action II Database
----------------------------------------------------------------------------------------------------------------------
Overall Incidence of Treatment Emergent Adverse Events by Drug 5.1.8 5.2.8 5.3.8
Relationship
----------------------------------------------------------------------------------------------------------------------
Overall Incidence of Treatment Emergent Adverse Events by Severity and 5.1.9 5.2.9 5.3.9
Drug Relationship
----------------------------------------------------------------------------------------------------------------------
Overall Incidence of Treatment Emergent Adverse Events of Special 5.1.10 5.2.10 5.3.10
Interest by Preferred Term
----------------------------------------------------------------------------------------------------------------------
Prevalence of Adverse Events of Special Interest in first 12 weeks by 2 5.1.11 5.2.11 5.3.11
week intervals
----------------------------------------------------------------------------------------------------------------------
Prevalence of Adverse Events of Special Interest by 3-month intervals 5.1.12 5.2.11 5.3.11
----------------------------------------------------------------------------------------------------------------------
Incidence of Treatment Emergent Adverse Events of Special Interest in 5.1.13 5.2.13 5.3.13
first 12 weeks by 2 week intervals (based on treatment-emergence
relative to the start of the interval)
----------------------------------------------------------------------------------------------------------------------
Incidence of Treatment Emergent Adverse Events of Special Interest by 3 5.1.14 5.2.14 5.3.14
month intervals (based on treatment-emergence relative to the start of
the interval)
----------------------------------------------------------------------------------------------------------------------
Cumulative Incidence of Treatment Emergent Adverse Events of Special 5.1.15 5.2.15 5.3.15
Interest in first 12 weeks by 2 week intervals (based on
treatment-emergence relative to the time of randomization)
----------------------------------------------------------------------------------------------------------------------
Cumulative Incidence of Treatment Emergent Adverse Events of Special 5.1.16 5.2.16 5.3.16
Interest by 3 month intervals (based on treatment-emergence relative to
the time of randomization)
----------------------------------------------------------------------------------------------------------------------
WITHDRAWALS DUE TO ADVERSE EVENTS
----------------------------------------------------------------------------------------------------------------------
Overall Incidence of Treatment Emergent Adverse Events Leading to 6.1.0 6.2.0 6.3.0
Permanent Discontinuation of Study Medication
----------------------------------------------------------------------------------------------------------------------
Overall Incidence of Treatment Emergent Adverse Events Leading to 6.1.1 6.2.1 6.3.1
Temporary Discontinuation of Study Medication
----------------------------------------------------------------------------------------------------------------------
Appendix 1 - Page 4
60
APPENDIX 1: PROPOSED LIST OF TABLES FOR THE ALTEON INTEGRATED SUMMARY OF SAFETY
----------------------------------------------------------------------------------------------------------------------
Integrated Summary of Safety (ISS)
Title
------------------------------------------
Integrated
Action I Action II Database
----------------------------------------------------------------------------------------------------------------------
Incidence of Treatment Emergent Adverse Events Leading to Permanent 6.1.2 6.2.2 6.3.2
Discontinuation in first 12 weeks by 2 week intervals
----------------------------------------------------------------------------------------------------------------------
Incidence of Treatment Emergent Adverse Events Leading to Permanent 6.1.3 6.2.3 6.3.3
Discontinuation by 3-month intervals
----------------------------------------------------------------------------------------------------------------------
Listing of Adverse Events Leading to Permanent Discontinuation of 6.1.4 6.1.4 6.1.4
Treatment (part of) (part of)
----------------------------------------------------------------------------------------------------------------------
SERIOUS ADVERSE EVENTS
----------------------------------------------------------------------------------------------------------------------
Overall Incidence of Treatment Emergent Serious Adverse Events 7.1.0 7.2.0 7.3.0
----------------------------------------------------------------------------------------------------------------------
Prevalence of Serious Adverse Events in first 12 weeks by 2 week 7.1.1 7.2.1 7.3.1
intervals
----------------------------------------------------------------------------------------------------------------------
Prevalence of Serious Adverse Events by 3-month intervals 7.1.2 7.2.2 7.3.2
----------------------------------------------------------------------------------------------------------------------
Incidence of Treatment Emergent Serious Adverse Events in first 12 weeks 7.1.3 7.2.3 7.3.3
by 2 week intervals
----------------------------------------------------------------------------------------------------------------------
Incidence of Treatment Emergent Serious Adverse Events by 3-month 7.1.4 7.2.4 7.3.4
intervals
----------------------------------------------------------------------------------------------------------------------
Listing of All Serious Adverse Events 7.1.5 7.1.5 7.1.5
(part of) (part of)
----------------------------------------------------------------------------------------------------------------------
DEATHS
----------------------------------------------------------------------------------------------------------------------
Incidence of all Deaths-- by Cause of Death (In the Action II study 8.1.0 8.2.0 8.3.0
separate section of table will be included giving cause of death as
adjudicated by the cardiovascular mortality and morbidity committee and
cause of death as reported on the serious adverse events report form)
----------------------------------------------------------------------------------------------------------------------
Listing of all Deaths 8.1.1 8.1.1 8.1.1
(part of) (part of) (part of)
----------------------------------------------------------------------------------------------------------------------
LABORATORY MEASURES
----------------------------------------------------------------------------------------------------------------------
Appendix 1 - Page 5
61
APPENDIX 1: PROPOSED LIST OF TABLES FOR THE ALTEON INTEGRATED SUMMARY OF SAFETY
----------------------------------------------------------------------------------------------------------------------
Integrated Summary of Safety (ISS)
Title
------------------------------------------
Integrated
Action I Action II Database
----------------------------------------------------------------------------------------------------------------------
Actual Values at Baseline and Change from Baseline Values Post-Baseline 9.1.0 9.2.0 9.3.0
at each visit - Hematology (Hemoglobin, Hematocrit, RBC Count, WBC
Count, Platelet Count, Reticulocyte Count, MCV + Iron parameters) [by
6 month intervals for IDB]
----------------------------------------------------------------------------------------------------------------------
Actual Values at Baseline and Change from Baseline Values Post-Baseline 9.1.1 9.2.1 9.3.1
at each visit - Liver Function Tests (Total Alkaline Phosphatase, Bone
Specific Alkaline Phosphatase, LDH, AST, ALT, Total Bilirubin) [by
6 month intervals for IDB]
----------------------------------------------------------------------------------------------------------------------
Actual Values at Baseline and Change from Baseline Values Post-Baseline 9.1.2 9.2.2 9.3.2
at each visit - Kidney Function Test (BUN) [by 6 month intervals for IDB]
----------------------------------------------------------------------------------------------------------------------
Actual Values at Baseline and Change from Baseline Values Post-Baseline 9.1.3 9.2.3 9.3.3
at each visit - Serum Protein and Uric Acid Levels (Total Protein,
Albumin, Uric Acid) [by 6 month intervals for IDB]
----------------------------------------------------------------------------------------------------------------------
Actual Values at Baseline and Change from Baseline Values Post-Baseline 9.1.4 9.2.4 9.3.4
at each visit - Electrolytes & CO2 [by 6 month intervals for IDB]
----------------------------------------------------------------------------------------------------------------------
Actual Values at Baseline and Change from Baseline Values Post-Baseline 9.1.5 9.2.5 9.3.5
at each visit - Lipids (Total Cholesterol, Triglycerides, LDL cholesterol
& HDL cholesterol) [by 6 month intervals for IDB]
----------------------------------------------------------------------------------------------------------------------
Actual Values at Baseline and Change from Baseline Values Post-Baseline 9.1.6 9.2.6 9.3.6
at each visit - Glycemic Control Tests (HbA1c, Fasting Blood Glucose)
[by 6 month intervals for IDB]
----------------------------------------------------------------------------------------------------------------------
Actual Values at Baseline and change from Baseline Values Post-Baseline 9.1.7 9.2.7 9.3.7
at each visit - Serological Markers (MPO, ANCA, ANA) [by 6 month
intervals for IDB]
----------------------------------------------------------------------------------------------------------------------
Appendix 1 - Page 6
62
APPENDIX 1: PROPOSED LIST OF TABLES FOR THE ALTEON INTEGRATED SUMMARY OF SAFETY
----------------------------------------------------------------------------------------------------------------------
Integrated Summary of Safety (ISS)
Title
------------------------------------------
Integrated
Action I Action II Database
----------------------------------------------------------------------------------------------------------------------
Actual Values and Actual Frequencies at Baseline and Change from 9.1.8 9.2.8 9.3.8
Baseline Values Post-Baseline and Change from Baseline Frequencies
Post-Baseline at each visit - Urinalysis (pH, Specific Gravity, Casts, ------------------------------------------
RBC, WBC, Glucose, Protein) [by 6 month intervals for IDB] Glucose & Protein will be presented only
in Action I & II study reports
----------------------------------------------------------------------------------------------------------------------
Actual Values at Baseline and Change from Baseline Values Post-Baseline 9.1.9 9.2.9 9.3.9
at each visit - 24 hour Urine Collections (Creatinine, Urea Nitrogen,
Calcium, Phosphorus, & Hydroxyproline) [by 6 month intervals for IDB]
----------------------------------------------------------------------------------------------------------------------
Incidence of Treatment-emergent Clinically Important Values overall and 9.1.10 9.2.10
by visit - Hematology [Overall includes separate counts for 1, 2, or 3
consecutive CI values. By visit results are for prevalence of CI values
for patients who are not CI at baseline]
----------------------------------------------------------------------------------------------------------------------
Incidence of Treatment-emergent Clinically Important Values overall and 9.1.11 9.2.11
by visit - Liver Function Tests [Overall includes separate counts for 1,
2, or 3 consecutive CI values. By visit results are for prevalence of CI
values for patients who are not CI at baseline]
----------------------------------------------------------------------------------------------------------------------
Incidence of Treatment-emergent Clinically Important Values overall and 9.1.12 9.2.12
by visit - Kidney Function Test [Overall includes separate counts for 1,
2, or 3 consecutive CI values. By visit results are for prevalence of CI
values for patients who are not CI at baseline]
----------------------------------------------------------------------------------------------------------------------
Incidence of Treatment-emergent Clinically Important Values overall and 9.1.13 9.2.13
by visit - Serum Protein and Uric Acid Levels [Overall includes separate
counts for 1, 2, or 3 consecutive CI values. By visit results are for
prevalence of CI values for patients who are not CI at baseline]
----------------------------------------------------------------------------------------------------------------------
Appendix 1 - Page 7
63
APPENDIX 1: PROPOSED LIST OF TABLES FOR THE ALTEON INTEGRATED SUMMARY OF SAFETY
----------------------------------------------------------------------------------------------------------------------
Integrated Summary of Safety (ISS)
Title
------------------------------------------
Integrated
Action I Action II Database
----------------------------------------------------------------------------------------------------------------------
Incidence of Treatment-emergent Clinically Important Values overall and 9.1.14 9.2.14
by visit - Electrolytes and CO2 [Overall includes separate counts for 1,
2, or 3 consecutive CI values. By visit results are for prevalence of
CI values for patients who are not CI at baseline]
----------------------------------------------------------------------------------------------------------------------
Incidence of Treatment-emergent Clinically Important Values overall and 9.1.15 9.2.15
by visit - Lipids [Overall includes separate counts for 1, 2, or 3
consecutive CI values. By visit results are for prevalence of CI values
for patients who are not CI at baseline]
----------------------------------------------------------------------------------------------------------------------
Incidence of Treatment-emergent Clinically Important Values overall and 9.1.16 9.2.16
9.1.16 9.2.16 by visit - Glycemic Control Tests [Overall includes separate
counts for 1, 2, or 3 consecutive CI values. By visit results are for
prevalence of CI values for patients who are not CI at baseline]
----------------------------------------------------------------------------------------------------------------------
Incidence of Treatment-emergent Clinically Important Values overall and 9.1.17 9.2.17
by visit - Serological Markers [Overall includes separate counts for
1, 2, or 3 consecutive CI values. By visit results are for prevalence of
CI values for patients who are not CI at baseline]
----------------------------------------------------------------------------------------------------------------------
Incidence of Significant Upper GI Endoscopy Measurements (▇▇▇▇▇ Scale 9.1.18 9.2.18
Score > 3) - overall and by visit
----------------------------------------------------------------------------------------------------------------------
Shift Tables Based on Normal Ranges (Baseline to Minimum, Maximum, & 9.1.19 9.2.19 9.3.10
Last value) - Hematology
----------------------------------------------------------------------------------------------------------------------
Shift Tables Based on Normal Ranges (Baseline to Minimum, Maximum, & 9.1.20 9.2.20 9.3.11
Last value) - Liver Function Tests
----------------------------------------------------------------------------------------------------------------------
Shift Tables Based on Normal Ranges (Baseline to Minimum, Maximum, & 9.1.21 9.2.21 9.3.12
Last value) - Kidney Function Test
----------------------------------------------------------------------------------------------------------------------
Appendix 1 - Page 8
64
APPENDIX 1: PROPOSED LIST OF TABLES FOR THE ALTEON INTEGRATED SUMMARY OF SAFETY
----------------------------------------------------------------------------------------------------------------------
Integrated Summary of Safety (ISS)
Title
------------------------------------------
Integrated
Action I Action II Database
----------------------------------------------------------------------------------------------------------------------
Shift Tables Based on Normal Ranges (Baseline to Minimum, Maximum, & 9.1.22 9.2.22 9.3.13
Last value) - Serum Protein and Uric Acid Levels
----------------------------------------------------------------------------------------------------------------------
Shift Tables Based on Normal Ranges (Baseline to Minimum, Maximum, & 9.1.23 9.2.23 9.3.14
Last value) - Electrolytes and CO2
----------------------------------------------------------------------------------------------------------------------
Shift Tables Based on Normal Ranges (Baseline to Minimum, Maximum, & 9.1.24 9.2.24 9.3.15
Last value) - Lipids
----------------------------------------------------------------------------------------------------------------------
Shift Tables Based on Normal Ranges (Baseline to Minimum, Maximum, & 9.1.25 9.2.25 9.3.16
Last value) - Glycemic Control Tests
----------------------------------------------------------------------------------------------------------------------
Shift Tables Based on Normal Ranges (Baseline to Minimum, Maximum, & 9.1.26 9.2.26 9.3.17
Last value) - Serological Markers
----------------------------------------------------------------------------------------------------------------------
Shift Tables Based on Normal Ranges (Baseline to Minimum, Maximum, & 9.1.27 9.2.27 9.3.18
Last value) - 24 hour Urine Collections
----------------------------------------------------------------------------------------------------------------------
Listing of Clinically Important Laboratory Abnormalities - Hematology A2.0 A2.1
----------------------------------------------------------------------------------------------------------------------
Listing of Clinically Important Laboratory Abnormalities - Liver A3.0 A3.1
Function Tests
----------------------------------------------------------------------------------------------------------------------
Listing of Clinically Important Laboratory Abnormalities - Kidney A4.0 A4.1
Function Test
----------------------------------------------------------------------------------------------------------------------
Listing of Clinically Important Laboratory Abnormalities - Serum Protein A5.0 A5.1
And Uric Acid Levels
----------------------------------------------------------------------------------------------------------------------
Listing of Clinically Important Laboratory Abnormalities - Electrolytes A6.0 A6.1
and CO2
----------------------------------------------------------------------------------------------------------------------
Listing of Clinically Important A7.0 A7.1
Laboratory Abnormalities - Lipids
----------------------------------------------------------------------------------------------------------------------
Listing of Clinically Important Laboratory Abnormalities - Glycemic A8.0 A8.1
control tests
----------------------------------------------------------------------------------------------------------------------
Appendix 1 - Page 9
65
APPENDIX 1: PROPOSED LIST OF TABLES FOR THE ALTEON INTEGRATED SUMMARY OF SAFETY
----------------------------------------------------------------------------------------------------------------------
Integrated Summary of Safety (ISS)
Title
------------------------------------------
Integrated
Action I Action II Database
----------------------------------------------------------------------------------------------------------------------
Listing of Clinically Important Laboratory Abnormalities - Serological A9.0 A9.1
Markers
----------------------------------------------------------------------------------------------------------------------
VITALS SIGNS
----------------------------------------------------------------------------------------------------------------------
Sitting ▇▇▇▇▇ ▇▇▇▇▇ - Systolic Blood Pressure - Actual Values at 10.1.0 10.2.0 10.3.0
Baseline and Change from Baseline at each visit [by 6 month intervals
for IDB]
----------------------------------------------------------------------------------------------------------------------
Sitting ▇▇▇▇▇ ▇▇▇▇▇ - Diastolic Blood Pressure - Actual Values at 10.1.1 10.2.1 10.3.1
Baseline and Change from Baseline at each visit [by 6 month intervals
for IDB]
----------------------------------------------------------------------------------------------------------------------
Sitting ▇▇▇▇▇ ▇▇▇▇▇ - Heart Rate - Actual Values at Baseline and Change 10.1.2 10.2.2 10.3.2
from Baseline [by 6 month intervals for IDB]
----------------------------------------------------------------------------------------------------------------------
Standing ▇▇▇▇▇ ▇▇▇▇▇ - Systolic Blood Pressure - Actual Values at 10.1.3 10.2.3 10.3.3
Baseline and Change from Baseline at each visit [by 6 month intervals
for IDB]
----------------------------------------------------------------------------------------------------------------------
Standing ▇▇▇▇▇ ▇▇▇▇▇ - Diastolic Blood Pressure - Actual Values at 10.1.4 10.2.4 10.3.4
Baseline and Change from Baseline at each visit [by 6 month intervals
for IDB]
----------------------------------------------------------------------------------------------------------------------
Standing ▇▇▇▇▇ ▇▇▇▇▇ - Heart Rate - Actual Values at Baseline and Change 10.1.5 10.2.5 10.3.5
from Baseline at each Visit [by 6 month intervals for IDB]
----------------------------------------------------------------------------------------------------------------------
Incidence of clinically relevant ▇▇▇▇▇ ▇▇▇▇▇ abnormalities overall and 10.1.6 10.2.6
by 6 month visits - (clinically relevant abnormalities will be based on
the FDA Division of Neuropharmacological Products guideline. Results at
6 month visits are based on cumulative incidence)
----------------------------------------------------------------------------------------------------------------------
Listing of clinically relevant ▇▇▇▇▇ ▇▇▇▇▇ abnormalities A10.0 A10.1
----------------------------------------------------------------------------------------------------------------------
ECGS
----------------------------------------------------------------------------------------------------------------------
QRS and Qtc ['c' subscript] - Actual values at Baseline and Change from 11.1.0 11.2.0
Baseline at each visit
----------------------------------------------------------------------------------------------------------------------
Appendix 1 - Page 10
66
APPENDIX 1: PROPOSED LIST OF TABLES FOR THE ALTEON INTEGRATED SUMMARY OF SAFETY
----------------------------------------------------------------------------------------------------------------------
Integrated Summary of Safety (ISS)
Title
------------------------------------------
Integrated
Action I Action II Database
----------------------------------------------------------------------------------------------------------------------
Shift Tables from Baseline at each Visit (Normal, Abnormal) (Overall and 11.1.1 11.2.1
for 9 groups of ECG parameters)
----------------------------------------------------------------------------------------------------------------------
Listing of abnormal ECG measurements A11.0 A11.1
----------------------------------------------------------------------------------------------------------------------
PHYSICAL EXAMINATION
----------------------------------------------------------------------------------------------------------------------
Physical Examination - Shifts from Baseline to Last Visit This table will be produced only for the
Action I and Action II study reports
----------------------------------------------------------------------------------------------------------------------
Weight - Change from Baseline to Each Visit This table will be produced only for the
Action I and Action II study reports
----------------------------------------------------------------------------------------------------------------------
DRUG-DEMOGRAPHIC INTERACTIONS
----------------------------------------------------------------------------------------------------------------------
Adverse events of special interest and the most common adverse events 12.1.0- 12.2.0- 12.3.0-
by: age category, sex, race, baseline BMI, smoking history, levels of 12.1.12 12.2.12 12.3.12
baseline serum creatinine, levels of baseline HbA1c, duration of diabetes
at baseline, levels of baseline GFR, baseline retinopathy (Y/N),
proteinuria, levels of baseline urine area nitrogen, levels of baseline LDL
----------------------------------------------------------------------------------------------------------------------
Serious adverse events by: age category, sex, race, baseline BMI, 12.1.13- 12.2.13- 12.3.13-
smoking history, levels of baseline serum creatinine, levels of baseline 12.1.25 12.2.25 12.3.25
HbA1c, duration of diabetes at baseline, levels of baseline GFR, baseline
retinopathy (Y/N), proteinuria, levels of baseline urine urea nitrogen,
levels of baseline LDL
----------------------------------------------------------------------------------------------------------------------
DRUG-DRUG INTERACTIONS
----------------------------------------------------------------------------------------------------------------------
Adverse events of special interest and the most common adverse events 13.1.0- 13.2.0- 13.3.0-
by: captopril, all ACE inhibitors (including captopril), calcium 13.1.4 13.2.10 13.3.4
channel antagonists, [beta symbol]-blockers, diuretics. In addition for the
Action II study these tables will also cover: metformin, troglitazone,
[alpha symbol]-glucosidase inhibitors, sulfonylureas, insulin, lipid
lowering agents, and Fen-Phen/Redux.
----------------------------------------------------------------------------------------------------------------------
Appendix 1 - Page 11
67
APPENDIX 1: PROPOSED LIST OF TABLES FOR THE ALTEON INTEGRATED SUMMARY OF SAFETY
----------------------------------------------------------------------------------------------------------------------
Integrated Summary of Safety (ISS)
Title
------------------------------------------
Integrated
Action I Action II Database
----------------------------------------------------------------------------------------------------------------------
Serious adverse events by: captopril, all ACE inhibitors (including 13.1.5- 13.2.11- 13.3.5-
captopril), calcium channel antagonists, [beta symbol]-blockers, 13.1.9 13.2.21 13.3.9
diuretics. In addition for the Action II study these tables will also
cover: metformin, troglitazone, [alpha symbol]-glucosidase inhibitors,
sulfonylureas, insulin, and lipid lowering agents
----------------------------------------------------------------------------------------------------------------------
DRUG-DISEASE INTERACTIONS
----------------------------------------------------------------------------------------------------------------------
Adverse events of special interest and the most common adverse events 14.1.0- 14.2.0- 14.3.0-
by: PVD, baseline cardiovascular morbidity (not present, active, not 14.1.3 14.2.3 14.3.3
active), uncontrolled hypertension (DBP >= 90), uncontrolled
hypertension (SBP >= 140)
----------------------------------------------------------------------------------------------------------------------
Serious adverse events by: PVD, baseline cardiovascular morbidity (not 14.1.4- 14.2.4- 14.3.4-
present, active, not active), uncontrolled hypertension (DBP >= 90), 14.1.7 14.2.7 14.3.7
uncontrolled hypertension (SBP >=140)
----------------------------------------------------------------------------------------------------------------------
FIGURES
----------------------------------------------------------------------------------------------------------------------
Plot of Number of SAEs versus Number of Patients at Risk over Time 1.1.0 1.2.0
----------------------------------------------------------------------------------------------------------------------
All safety tables are based on the ITT population
Appendix 1 - Page 12
68
APPENDIX 2: PROPOSED LIST OF TABLES AND FIGURES FOR THE ALTEON INTEGRATED
SUMMARY OF EFFICACY, TOGETHER WITH A PROPOSED LIST OF THE
CORRESPONDING TABLES AND FIGURES IN ACTION I AND ACTION II
STUDY REPORTS
Table Numbering Conventions:
1. All tables have numbers of the form X.X.
2. The first level (1.X, 2.X, etc) represents the nature of the data,
e.g., Patient Descriptives, Efficacy, etc.
4. The second level (X.1, X.2, etc) represents the table number within
this type of data.
5. Missing table numbers in any column indicates that the corresponding
tables will not be produced for that document (ISE, Action I Study
Report, or Action II Study Report).
--------------------------------------------------------------------------------------------------------------------------------
Table number Table number Table number
Title in ISE in Action I in Action II
(based on Study Report Study Report
Action I)
--------------------------------------------------------------------------------------------------------------------------------
PATIENT DESCRIPTIVES
--------------------------------------------------------------------------------------------------------------------------------
Patient disposition - Study completion and treatment cessation information 1.0 1.0 1.0
- Enrolled patients
--------------------------------------------------------------------------------------------------------------------------------
Overview of analysis populations (This table will contain information 1.1 1.1 1.1
regarding the number of ITT, Safety, and Per Protocol patients at each
visit, as well as the number that are valuable for the primary efficacy
parameter.)
--------------------------------------------------------------------------------------------------------------------------------
Listing of patients excluded from the ITT population 1.2 1.2 1.2
--------------------------------------------------------------------------------------------------------------------------------
Listing of patients excluded from the Per Protocol population 1.3 1.3 1.3
--------------------------------------------------------------------------------------------------------------------------------
Patient disposition by center - Number of patients enrolled, evaluated, 1.4 1.4 1.4
ceased treatment, and dropped out at each center - ITT population
--------------------------------------------------------------------------------------------------------------------------------
Patient disposition by visit - ITT population & Per Protocol populations 1.5 1.5 1.5
(This table will show the number of patients on-treatment at the protocol
correct dose, on-treatment at protocol incorrect dose, off-treatment, dropped
out, and lost to follow-up at each visit for each treatment)
--------------------------------------------------------------------------------------------------------------------------------
Appendix 2 - Page 1
69
APPENDIX 2: PROPOSED LIST OF TABLES AND FIGURES FOR THE ALTEON INTEGRATED
SUMMARY OF EFFICACY, TOGETHER WITH A PROPOSED LIST OF THE
CORRESPONDING TABLES AND FIGURES IN ACTION I AND ACTION II
STUDY REPORTS
--------------------------------------------------------------------------------------------------------------------------------
Table number Table number Table number
Title in ISE in Action I in Action II
(based on Study Report Study Report
Action I)
--------------------------------------------------------------------------------------------------------------------------------
Number of patients with major protocol deviations - ITT 1.6 1.6 1.6
--------------------------------------------------------------------------------------------------------------------------------
COMPLIANCE AND EXPOSURE TO STUDY MEDICATION
--------------------------------------------------------------------------------------------------------------------------------
Total duration of exposure to study medication overall and by 6-month 2.0 - 2.1 2.0 - 2.1 2.0 - 2.1
intervals (not accounting for gaps in study medication administration) -
ITT & Per Protocol populations
--------------------------------------------------------------------------------------------------------------------------------
Duration of exposure to study medication overall and by 6-month intervals 2.2 - 2.3 2.2 - 2.3 2.2 - 2.3
(accounting for gaps in study medication administration) - ITT & Per
Protocol populations
--------------------------------------------------------------------------------------------------------------------------------
Dose titrations - ITT & per protocol populations (including information on 2.4 - 2.5 2.4 - 2.5 2.4 - 2.5
the number of times the dose was changed, number of times patient was
taken off study medication, overall and by reason)
--------------------------------------------------------------------------------------------------------------------------------
Study medication compliance - ITT population (This table will show the 2.6 2.6 2.6
number of patients in each of the following categories: < 80% compliance,
80% - 120% compliance, and > 120% compliance)
--------------------------------------------------------------------------------------------------------------------------------
DEMOGRAPHICS, BACKGROUND CHARACTERISTICS, AND MEDICAL HISTORY
--------------------------------------------------------------------------------------------------------------------------------
Patient demographics - ITT & Per Protocol populations (age, age category, 3.0 - 3.1 3.0 - 3.1 3.0 - 3.1
sex, race, weight, weight category, height, BMI)
--------------------------------------------------------------------------------------------------------------------------------
Appendix 2 - Page 2
70
APPENDIX 2: PROPOSED LIST OF TABLES AND FIGURES FOR THE ALTEON INTEGRATED
SUMMARY OF EFFICACY, TOGETHER WITH A PROPOSED LIST OF THE
CORRESPONDING TABLES AND FIGURES IN ACTION I AND ACTION II
STUDY REPORTS
--------------------------------------------------------------------------------------------------------------------------------
Table number Table number Table number
Title in ISE in Action I in Action II
(based on Study Report Study Report
Action I)
--------------------------------------------------------------------------------------------------------------------------------
Background Characteristics - ITT & Per Protocol populations (smoking, 3.2-3.3 3.2-3.3 3.2-3.3
duration of diabetes, Baseline HbA1c, Baseline serum creatinine, Baseline
GFR, Baseline proteinuria, Baseline 24-hour urine creatinine clearance, Systolic
BP, Systolic BP category, Diastolic BP, Diastolic BP category, Insulin type,
Insulin daily dose, Baseline Triglycerides, Baseline Total cholesterol, Baseline
HDL Cholesterol, Baseline LDL cholesterol, Total cholesterol to HDL ratio, and
for Action II only - cardiovascular morbidity)
--------------------------------------------------------------------------------------------------------------------------------
Medical History - ITT & Per Protocol population (including body system 3.4-3.5 3.4-3.5 3.4-3.5
categories and several groups of parameters from the Baseline ECG form)
--------------------------------------------------------------------------------------------------------------------------------
PRIOR AND CONCOMITANT MEDICATIONS
--------------------------------------------------------------------------------------------------------------------------------
Incidence of prior medications at baseline - ITT population A1.0 A1.0
--------------------------------------------------------------------------------------------------------------------------------
Incidence of concomitant medications taken prior to randomization - ITT A2.0 A2.0
population
--------------------------------------------------------------------------------------------------------------------------------
Incidence of key concomitant medications taken during the double-blind 4.0 4.0 4.0
treatment period - ITT population [ACE inhibitors, [beta symbol]-blockers,
diuretics, Calcium channel antagonists, insulin (overall and by type),
each prohibited medication + for Action II only: troglitazone,
sulfonylureas, metformin, [alpha symbol]-glucosidase inhibitors, lipid
lowering agents]
--------------------------------------------------------------------------------------------------------------------------------
Incidence of concomitant medications taken during the double-blind A3.0 A3.0
treatment period - ITT population
--------------------------------------------------------------------------------------------------------------------------------
EFFICACY MEASURES
--------------------------------------------------------------------------------------------------------------------------------
Appendix 2 - Page 3
71
APPENDIX 2: PROPOSED LIST OF TABLES AND FIGURES FOR THE ALTEON INTEGRATED
SUMMARY OF EFFICACY, TOGETHER WITH A PROPOSED LIST OF THE
CORRESPONDING TABLES AND FIGURES IN ACTION I AND ACTION II
STUDY REPORTS
--------------------------------------------------------------------------------------------------------------------------------
Table number Table number Table number
Title in ISE in Action I in Action II
(based on Study Report Study Report
Action I)
--------------------------------------------------------------------------------------------------------------------------------
Time to first doubling of serum creatinine verified by a confirmation 5.0-5.1 5.0-5.1 5.0-5.1
visit - ITT & Per Protocol populations (This table will give logrank p-values
both the stratified by pooled center and unstratified, as well as ▇▇▇▇▇▇-▇▇▇▇▇
estimates of survival probabilities at 3 month intervals.)
--------------------------------------------------------------------------------------------------------------------------------
Time to composite event of doubling of serum creatinine or end stage renal 5.2-5.3 5.2-5.3 5.2-5.3
disease (maintenance dialysis or transplant) - ITT & Per Protocol
populations (logrank test)
--------------------------------------------------------------------------------------------------------------------------------
Time to first doubling of serum creatinine verified by a confirmation 5.4 5.4 5.4
visit-- results from interim analyses - ITT population (log rank test, KM
estimate of survival)
--------------------------------------------------------------------------------------------------------------------------------
Time to composite event of end stage renal disease (dialysis or 5.5-5.6 5.5-5.6 5.5-5.6
transplantation) or death - ITT & Per Protocol populations (logrank test)
--------------------------------------------------------------------------------------------------------------------------------
Time to all cause mortality - ITT & Per Protocol populations 5.7-5.8 5.7-5.8 5.7-5.8
--------------------------------------------------------------------------------------------------------------------------------
Time to cardiovascular mortality or morbidity - ITT & Per Protocol 5.9-5.10
population
--------------------------------------------------------------------------------------------------------------------------------
Time to end stage renal disease (dialysis or transplantation) - ITT & Per 5.11-5.12
protocol population
--------------------------------------------------------------------------------------------------------------------------------
Rate of change in log GFR determined by iothalamate clearance - ITT & Per 5.9-5.10 5.9-5.10 5.13-5.14
Protocol populations (2-stage random effects model)
--------------------------------------------------------------------------------------------------------------------------------
Rate of change in serum creatinine - ITT & per Protocol Populations 5.11-5.12 5.11-5.12 5.15-5.16
(2-stage random effects model)
--------------------------------------------------------------------------------------------------------------------------------
Appendix 2 - Page 4
72
APPENDIX 2: PROPOSED LIST OF TABLES AND FIGURES FOR THE ALTEON INTEGRATED
SUMMARY OF EFFICACY, TOGETHER WITH A PROPOSED LIST OF THE
CORRESPONDING TABLES AND FIGURES IN ACTION I AND ACTION II
STUDY REPORTS
--------------------------------------------------------------------------------------------------------------------------------
Table number Table number Table number
Title in ISE in Action I in Action II
(based on Study Report Study Report
Action I)
--------------------------------------------------------------------------------------------------------------------------------
5.13-5.14 5.13-5.14 5.17-5.18
Rate of decline in estimated creatinine clearance (calculated by the
Cockrauft & ▇▇▇▇▇ method) - ITT & Per Protocol populations (2-stage random
effects model)
--------------------------------------------------------------------------------------------------------------------------------
Rate of change in measured creatinine clearance from 24-hour urine 5.15-5.16 5.15-5.16 5.19-5.20
collection - ITT & per protocol populations (2-stage random effects
model)
--------------------------------------------------------------------------------------------------------------------------------
Change from baseline in urinary protein excretion from 24-hour urine 5.17-5.18 5.17-5.18 5.21-5.22
5.17-5.18 5.17-5.18 5.21-5.22 collection - ITT & Per Protocol populations
(Repeated measures over all time points as well as testing at each time point)
--------------------------------------------------------------------------------------------------------------------------------
Change from baseline to endpoint in retinal data (Diabetic Retinopathy) 5.19-5.20 5.19-5.20 5.23-5.24
overall and stratified by prior photo coagulation - ITT & Per Protocol
populations
--------------------------------------------------------------------------------------------------------------------------------
Proportion changing from Baseline to Endpoint by at least 3 units - ITT & 5.21-5.22 5.21-5.22 5.25-5.26
Per Protocol populations
--------------------------------------------------------------------------------------------------------------------------------
Shifts from baseline to endpoint for individual retinal events - ITT & Per 5.23-5.24 5.23-5.24 5.27-5.28
Protocol populations
--------------------------------------------------------------------------------------------------------------------------------
Shifts from baseline to endpoint-- retinal slit lamp examinations - ITT & 5.25-5.26 5.25-5.26 5.29-5.30
Per Protocol populations
--------------------------------------------------------------------------------------------------------------------------------
Drug-Demographic Interactions for the Primary Efficacy Parameter of Time
to First Doubling of Serum Creatinine Verified by a Confirmation Visit
(ITT Population only)
--------------------------------------------------------------------------------------------------------------------------------
Appendix 2 - Page 5
73
APPENDIX 2: PROPOSED LIST OF TABLES AND FIGURES FOR THE ALTEON INTEGRATED
SUMMARY OF EFFICACY, TOGETHER WITH A PROPOSED LIST OF THE
CORRESPONDING TABLES AND FIGURES IN ACTION I AND ACTION II
STUDY REPORTS
--------------------------------------------------------------------------------------------------------------------------------
Table number Table number Table number
Title in ISE in Action I in Action II
(based on Study Report Study Report
Action I)
--------------------------------------------------------------------------------------------------------------------------------
These tables will cover: age category, sex, race, baseline BMI, smoking 6.0-6.12 6.0-6.12 6.0-6.12
history, levels of baseline serum creatinine, levels of baseline HbA1c,
duration of diabetes at baseline, levels of baseline GFR, baseline retinopathy
(Y/N), proteinuria, levels of baseline urine urea nitrogen, levels of baseline
LDL
--------------------------------------------------------------------------------------------------------------------------------
DRUG-DRUG INTERACTIONS FOR THE PRIMARY EFFICACY PARAMETER OF TIME TO FIRST
DOUBLING OF SERUM CREATININE VERIFIED BY A CONFIRMATION VISIT (ITT
POPULATION ONLY)
--------------------------------------------------------------------------------------------------------------------------------
These tables will cover: captopril, all ACE inhibitors (including 7.0-7.4 7.0-7.4 7.0-7.10
captopril), calcium channel antagonists, [beta symbol]-blockers,
diuretics. In addition for the Action II study these tables will also
cover: metformin, troglitazone, [alpha symbol]-glucosidase inhibitors,
sulfonylureas, insulin, and lipid lowering agents
--------------------------------------------------------------------------------------------------------------------------------
DRUG-DISEASE INTERACTIONS FOR THE PRIMARY EFFICACY PARAMETER OF TIME TO
FIRST DOUBLING OF SERUM CREATININE VERIFIED BY A CONFIRMATION VISIT (ITT
POPULATION ONLY)
--------------------------------------------------------------------------------------------------------------------------------
These tables will cover: PVD, baseline cardiovascular morbidity (not 8.0-8.3 8.0-8.3 8.0-8.3
present, active, not active), uncontrolled hypertension (DBP > = 90),
uncontrolled hypertension (SBP >= 140)
--------------------------------------------------------------------------------------------------------------------------------
FIGURES
--------------------------------------------------------------------------------------------------------------------------------
▇▇▇▇▇▇-▇▇▇▇▇ plot of time to first doubling of Serum Creatinine verified 1.0-1.1 1.0-1.1 1.0-1.1
by a confirmation visit - ITT & Per Protocol populations
--------------------------------------------------------------------------------------------------------------------------------
Appendix 2 - Page 6
74
APPENDIX 2: PROPOSED LIST OF TABLES AND FIGURES FOR THE ALTEON INTEGRATED
SUMMARY OF EFFICACY, TOGETHER WITH A PROPOSED LIST OF THE
CORRESPONDING TABLES AND FIGURES IN ACTION I AND ACTION II
STUDY REPORTS
--------------------------------------------------------------------------------------------------------------------------------
Table number Table number Table number
Title in ISE in Action I in Action II
(based on Study Report Study Report
Action I)
--------------------------------------------------------------------------------------------------------------------------------
▇▇▇▇▇▇-▇▇▇▇▇ plot of time to composite event of end stage renal disease 1.2-1.3 1.2-1.3 1.2-1.3
(maintenance dialysis or transplant) or doubling of serum creatinine - ITT
& Per Protocol populations
--------------------------------------------------------------------------------------------------------------------------------
▇▇▇▇▇▇-▇▇▇▇▇ plot of time to earlier of mortality, dialysis, or 1.4-1.5 1.4-1.5 1.4-1.5
transplantation - ITT & Per Protocol populations
--------------------------------------------------------------------------------------------------------------------------------
▇▇▇▇▇▇-▇▇▇▇▇ plot of time to all-cause mortality - ITT & per protocol 1.6-1.7 1.6-1.7 1.6-1.7
populations
--------------------------------------------------------------------------------------------------------------------------------
▇▇▇▇▇▇-▇▇▇▇▇ plot of time to event of end stage renal disease or death - 1.8-1.9 1.8-1.9 1.8-1.9
ITT & per protocol populations
--------------------------------------------------------------------------------------------------------------------------------
Plot of rate of change in serum creatinine over time - ITT & per protocol 1.10-1.11 1.10-1.11 1.10-1.11
populations
--------------------------------------------------------------------------------------------------------------------------------
Plot of rate of change in estimated creatinine clearance over time - ITT & 1.12-1.13 1.12-1.13 1.12-1.13
per protocol populations
--------------------------------------------------------------------------------------------------------------------------------
Plot of rate of change in measured creatinine clearance over time - ITT & 1.14-1.15 1.14-1.15 1.14-1.15
per protocol populations
--------------------------------------------------------------------------------------------------------------------------------
Plot of rate of change in GFR over time determined by iothalamate 1.16-1.17 1.16-1.17 1.16-1.17
clearance - ITT & per protocol populations
--------------------------------------------------------------------------------------------------------------------------------
Appendix 2 - Page 7
75
APPENDIX 3: SUMMARY OF NDA SECTIONS, PRIMARY RESPONSIBILITIES, ESTIMATED
NUMBER OF VOLUMES AND DATE OF FINAL RECEIPT
--------------------------------------------------------------------------------------------------------------------------
NDA ITEM NO. PRIMARY ESTIMATE NO. OF FINAL DOCUMENTS
RESPONSIBILITY VOLUMES RECEIVED AT QUINTILES
--------------------------------------------------------------------------------------------------------------------------
Item 1: Index (Table of Contents) Quintiles 1 N/A
--------------------------------------------------------------------------------------------------------------------------
Item 2: Labeling Alteon 0.25 *
--------------------------------------------------------------------------------------------------------------------------
Item 3: Overall NDA Summary Quintiles/ 0.75 *
Alteon(1)
--------------------------------------------------------------------------------------------------------------------------
Item 4: CMC Section Alteon
Drug Substance 1 *
(all sections except Physical &
Chemical Characteristics)
Physical & Chemical Characteristics *
Drug Product (all sections except Methods of 2 *
Manufacturing & Pkg and Stability)
Methods of Manufacturing & Pkg *
Stability *
Methods Validation and Samples 1 *
Environmental Assessment *
--------------------------------------------------------------------------------------------------------------------------
Item 5: Nonclinical Pharmacology & Toxicology Alteon 50? *
Technical Summary & References *
Individual Study Reports *
--------------------------------------------------------------------------------------------------------------------------
Item 6: Human Pharmacokinetics & Bioavailability Alteon 20? *
Technical Summary & References *
Individual Study Reports
Phase I single, oral ascending dose (1987) *
CPK88003 *
RPK89002 *
AGC89005 *
AGC89008 *
Multiple dose safety & PK in volunteers (1996) *
AGC9011 *
--------------------------------------------------------------------------------------------------------------------------
Item 7: Microbiology Section N/A N/A N/A
--------------------------------------------------------------------------------------------------------------------------
* Confidential Treatment Requested
Appendix 3 - Page 1
76
APPENDIX 3: SUMMARY OF NDA SECTIONS, PRIMARY RESPONSIBILITIES, ESTIMATED
NUMBER OF VOLUMES AND DATE OF FINAL RECEIPT
-------------------------------------------------------------------------------------------------------------------------------
NDA ITEM NO. PRIMARY ESTIMATE NO. OF FINAL DOCUMENTS
RESPONSIBILITY VOLUMES RECEIVED AT QUINTILES
-------------------------------------------------------------------------------------------------------------------------------
Item 8: Clinical Data Section Quintiles
Overall Summary (include items designated with "*" below) Quintiles/ 1 *
Alteon(2)
*Clinical Pharmacology Summary
Individual Study Reports (completed studies) Quintiles 1 *
AGPR0002 (ACTION I)
AGPR0015 (Microalbuminuria) Quintiles 10 *
AGPR0016 (Dyslipidemia) Alteon 1? *
AGC89003 (Phase II) Alteon 1? *
AGC89006 (Phase II) Alteon 1? *
Alteon 1? *
*Brief Synopses (protocol and CRF for ongoing studies)
AGPR00014 (ESRD)
*Safety Report (discontinued studies) Alteon 1 *
AGPR0009 (ACTION II)
Patient Narratives (1200+) Quintiles 10 *
Integrated Summary of Safety
Integrated Summary of Efficacy Alteon 4+ *
*Summary of Risk/Benefit Quintiles 10 *
Literature Review/References Quintiles 5 *
Quintiles/Alteon 25 *
Alteon 5 *
--------------------------------------------------------------------------------------------------------------------------
Item 9: 120-Day Safety Update Alteon or N/A N/A
Quintiles
--------------------------------------------------------------------------------------------------------------------------
Item 10: Statistical Section Quintiles 1 *
--------------------------------------------------------------------------------------------------------------------------
Item 11: Case Report Tabulations N/A N/A N/A
(requesting waiver from FDA)
--------------------------------------------------------------------------------------------------------------------------
Item 12: Case Report Forms Alteon 1 *
(submitting images)
--------------------------------------------------------------------------------------------------------------------------
Item 13: Patent Information Alteon (incl in Vol 1) *
--------------------------------------------------------------------------------------------------------------------------
Item 14: Patient Certification Alteon (incl in Vol 1) *
--------------------------------------------------------------------------------------------------------------------------
1. Alteon will supply Chemistry Manufacturing and Controls, Nonclinical
Pharmacology & Toxicology, and Human Pharmacokinetics & Bioavailability
portions of the Overall NDA Summary.
2. Alteon will supply the Human Pharmacokinetics & Bioavailability
portions of the Clinical Data Overall Summary
* Confidential Treatment Requested
Appendix 3 - Page 2
