Sender:
`
`Wheeler William </O=CARTER-
`W ALLACE/OU=CRANMAIL/CN=RECIPIENTS/CN=EXCHANGE/CN=WWHEELER>
`Sent:
`Wednesday, October 30, 2002 6:47:59 PM
`Recipient:
`Klein Barbara <BKlein@medpointeinc.com>
`Subject:
`Life Cycle Management Astelin Projects
`Attachments: Life Cycle Management Astelin Projects
`
`Barabara: here's the LCM document for distribution. Thanks, Bill
`Life Cycle Management Astelin Projects
`
`PLAINTIFFS'
`TRIAL EXHIBIT
`PTX1006 e
`
`xhibitsticker.com
`
`MEDA_APTX02875673
`
`HIGHLY CONFIDENTIAL-
`SUBJECT TO STIPULATED PROTECTIVE ORDER
`
`PTX1006-00001
`
`1
`
`CIP2056
`Argentum Pharmaceuticals LLC v. Cipla Ltd.
`IPR2017-00807
`
`CIPLA LTD. EXHIBIT 2032 PAGE 1
`
`

`

`AS TELl~ NASAL SPRAY
`
`LIFE CYCLE MANAGEMENT PROJECTS
`
`(Preliminary Plan)
`
`HIGHLY CONFIDENTIAL-
`SUBJECT TO STIPULATED PROTECTIVE ORDER
`
`MEDA_APTX0287567 4
`
`PTX1006-00002
`
`2
`
`CIPLA LTD. EXHIBIT 2032 PAGE 2
`
`

`

`Table of Contents
`
`Page
`ASTELIN Project
`Packaging Configuration Projects ...................... ............... ........... ... .
`1
`2
`Pediatric Packaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...
`V-Bottom Bottle/Cap Configuration-Trade (30.0 mL) . . . . . . . . . . . . . . . . . . . . . . 3
`V-Bottom Bottle/Pump Configuration-Trade (30.0 mL) . . . . . . . . . . . . . .. . .. . 4
`V-Bottom Bottle-Sample (5 mL) .. . .. . . .. .. . .. . . .. .. . .. . .. . . . . .. .. .. .. . .. . .. ...
`5
`Calmar-Albert Pump .. . .. . . .. .. . .. . .. . .. . . .. .. . .. . .. . .. . . .. .. . .. . .. . .. . .. . . .. .. ..
`6
`Formulations Projects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
`Astelin/Steroid Combination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
`Taste Masking- Meet Current Specifications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
`New Optimized Formulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 0
`Clinical Programs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
`One Spray per Nostril bid (Supplemental NDA) . . . . . . . . . . . . . . . . . . . . . . . . . . . ..
`12
`Perennial Allergic Rhinitis (Supplemental NDA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
`Protocol 415 (Fallow-on to Protocol 414 Claritin Failure Trial) . . . . . . . . . . . 14
`SAR and Asthma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
`Somnolence/Cognitive Function Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
`Nasal Polyps (Pilot study) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
`Pediatric Labeling (children 2 to 4 years of age) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
`Nonallergic Asthma (NIH study) .. . .. .. .. .. .. .. .. . .. . .. . .. .. .. . .. .. . .. .. .. .. .. .. 19
`Preclinical Program . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
`Otitis Media (Animal Model) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
`
`HIGHLY CONFIDENTIAL-
`SUBJECT TO STIPULATED PROTECTIVE ORDER
`
`MEDA_APTX02875675
`
`PTX1006-00003
`
`3
`
`CIPLA LTD. EXHIBIT 2032 PAGE 3
`
`

`

`PACKAGING CONFIGURATION PROJECTS
`PACKAGING CONFIGURATION PROJECTS
`
`- 1 -
`
`HIGHLY CONFIDENTIAL-
`HIGHLY CONFIDENTIAL -
`4
`SUBJECT TO STIPULATED PROTECTIVE ORDER
`SUBJECT TO STIPULATED PROTECTIVE ORDER
`
`MEDA_APTX02875676
`MEDA_APTX02875676
`
`PTX1006-00004
`
`CIPLA LTD. EXHIBIT 2032 PAGE 4
`
`PTX1006-00004
`
`4
`
`CIPLA LTD. EXHIBIT 2032 PAGE 4
`
`

`

`Product: ASTELIN NASAL SPRAY
`
`Project: Pediatric Packaging
`
`Objective: To develop a new Astelin Nasal Spray packaging configuration that will be designated as
`"Pediatric" containing a single l7mL flat bottom bottle and a single current VP3 Valois pump.
`
`Background: FDA approval has been obtained for the use of Astelin Nasal Spray in children 5 to 11 years
`of age. The current packaging configuration provides twice the product volume for pediatric patients,
`compared to adults (based on the differences in dose). Therefore, rather than 2 x 17mL bottles and one
`pump provided in an adult trade carton, one 17mL bottle and one pump will be provided in a pediatric trade
`carton. Development of this pediatric package involves labeling revisions to the following: package insert,
`patient instructions, 17mL bottle label, trade carton.
`
`Feasibility: High
`
`Likelihood of Success: High.
`
`Time: There are three possible scenarios which would affect timing:
`(1) Annual Reportable Change: internal revision of the product labeling to simply remove all references to
`two 17 mL bottles and any artwork geared toward adults, making no reference to a "Pediatric Package".
`This change could be implemented as soon as final printed labeling (FPL) is available and would only
`require notification to FDA in the subsequent NDA Annual Report.
`(2) Changes Being Effected (CBE) Supplement or Annual Reportable: internal revision of the labeling to
`remove all references to two 17mL bottles and include a reference to "Pediatric Package" and artwork
`geared toward children on the bottle and/or carton regarding "Pediatric Package" . Depending upon the
`extent of the pediatric package marketing spin (to be evaluated by Regulatory), this change could either be
`handled as indicated in 1) above, or it would require the submission of a CBE. For the CBE, draft labeling
`would be submitted in a supplement which could be implemented after 30 days, unless FDA objected.
`(3) CBE or Prior Approval Supplement (PAS): in addition to internal labeling changes to remove all
`references to two 17mL bottles, addition of artwork geared toward children and indication of "Pediatric
`Package", if a value added piece (to be evaluated by Regulatory) is to be included, submission of a CBE or
`PAS would be required. FDA approval (PAS) would be required in almost any case of the use of value
`added material.
`
`Cost: A cost of approximately $1000.00 per individual piece of product labeling will be incurred. Total
`cost approximately $5000.00. Cost for destruction of existing label inventory TBD.
`
`Milestones/Go no Go Decisions:
`Milestone
`Resolution of the issues concerning the Sepracor contract
`Determination of the changes to be incorporated
`Determination of short vs long-term use of pediatric package*
`Determination of FDA submission requirements
`Initiation of internal approval process for labeling components
`Completion of labeling approval process
`Submission to FDA
`Launch
`
`Timing
`TBD
`TBD
`TBD
`BD
`1-2 weeks
`2-3 weeks
`TBD
`TBD
`
`Cost
`TBD
`TBD
`TBD
`TBD
`TBD
`TBD
`TBD
`TBD
`
`Promotahilitv: Labeling change could be used to support safety and convenience/cost savings in pediatric
`patients.
`
`Market Forecast:
`
`*Based upon recent market "models". Links into life cycle for V-bottom bottle configuration.
`
`- 2-
`
`HIGHLY CONFIDENTIAL-
`SUBJECT TO STIPULATED PROTECTIVE ORDER
`
`MEDA_APTX02875677
`
`PTX1006-00005
`
`5
`
`CIPLA LTD. EXHIBIT 2032 PAGE 5
`
`

`

`Product: ASTELIN NASAL SPRAY
`
`Project: V-Bottom Bottle/Cap Configuration-Trade (30.0 mL)
`
`Objective: To provide a back-up for the currently approved v-bottom bottle/pump
`configuration in the event that the manufacturability of the bottle/pump configuration is
`not achievable either from an engineering or specification standpoint
`
`Background: Historically the 17mL Owens Brockway flat bottom bottle/cap
`configuration has not been associated with high particulate levels. The V -bottom bottle
`has had higher particulate levels. Data has also demonstrated that the placement of a
`spigot ring pump on a V -bottom bottom at release introduces a significant level of
`particulates that could potentially be outside the current specifications. These data again
`suggest that the major source of particulates is from the pump and efforts would need to
`be initiated to reduce the associated particulates.
`
`Feasibilitv: The feasibility of this configuration will depend on obtaining a suitable cap
`and future studies to determine the particulate levels when the cap is mechanically placed
`on the V-bottom bottle.
`
`Likelihood of Success: High. If the particulate level from the pump component can be
`significantly reduced and the mechanical placement of the pump cannot be achieved, then
`this configuration would be a suitable back-up. Otherwise this project could potentially
`have the same particulate issues as the bottle/cap configuration.
`
`Time: 18-28 months from the acquisition of suitable packaging components
`
`Cost: Milestones/Go no Go Decisions: ...
`
`Feasibility
`Stability (Decatur)
`FDA Submission
`FDA Approval
`
`3 months
`12 months
`3 months
`6-9 months
`
`$17,500
`$35,000
`
`Promotability: New package configuration will be fully promotable.
`
`Market Forecast:
`
`- 3 -
`
`HIGHLY CONFIDENTIAL-
`SUBJECT TO STIPULATED PROTECTIVE ORDER
`
`MEDA_APTX02875678
`
`PTX1006-00006
`
`6
`
`CIPLA LTD. EXHIBIT 2032 PAGE 6
`
`

`

`Product: ASTELIN NASAL SPRAY
`
`Project: V-Bottom Bottle/Pump Configuration-Trade (30.0 mL)
`
`Objective: To provide Astelin in a new package configuration that would be more
`patient friendly, require only one bottle per box/Rx, reduce cost of goods sold and
`comply with Phase IV commitment made to FDA to reduce particulates.
`
`Background: The 30.0 mL V-bottom bottle/pump packaging configuration was
`approved via an SNDA. The placement of the pump during manufacturing was
`performed manually and resulted in particulate levels that conformed to release
`specifications of the current 17 mL configuration. The pump placing equipment at
`Decatur was never evaluated until September 2002 to determine if the mechanical
`installation of the pump would be able to result in acceptable particulate levels at release.
`The September 2002 feasibility study failed to achieve acceptable particulate levels. In
`addition, a considerable amount of operator intervention was necessary to remedy poor
`placement of the pumps into the bottle. A project team has been formed and an intense
`investigation of the entire process is being conducted. This investigation is focusing on
`the equipment and the two packaging components (bottle/pump). Historically the pump
`has been the major source of particulates and multiple attempts have been made in the
`past to reduce the amount of particulates.
`
`Feasibilitv: Will be determined following engineering evaluation ofbottle cleaning and
`pump placer equipment and all possibilities implemented to reduce the number of
`particulates associated with each packaging component.
`
`Likelihood of Success: High. However, if the amount of particulates associated with
`the pump cannot be significantly reduced by the manufacturer and during the
`manufacturing process, a successful outcome does not seem likely.
`
`Time: 6-9 months if the components for additional feasibility studies to be conducted in
`Jan/Feb are ordered now
`
`Cost:Milestones/Go no Go Decisions: ...
`
`Configuration Approved
`Ordering Components
`Successful Feasibility Study
`Analysis of 3 PQ Batches (Stability)
`Available for Launch
`
`FDA approval
`Oct/Nov 2002
`2-3 months
`9 months
`10 months
`
`$170,000
`
`$170,000
`
`Promotability: New package configuration will be fully promotable
`
`Market Forecast:
`
`- 4-
`
`HIGHLY CONFIDENTIAL-
`SUBJECT TO STIPULATED PROTECTIVE ORDER
`
`MEDA_APTX02875679
`
`PTX1006-00007
`
`7
`
`CIPLA LTD. EXHIBIT 2032 PAGE 7
`
`

`

`Product: ASTELIN NASAL SPRAY
`
`Project: V-Bottom Bottle-Sample (5 mL)
`
`Objective: To provide Astelin in a new sample package configuration that would be
`more patient friendly, reduce cost of goods sold and comply with Phase IV commitment
`made to FDA to reduce particulates.
`
`Background: The 5 mL V -bottom bottle sample was approved via an SNDA The
`primary reason for this bottle was to allow use of the same spigot ring pump for both
`trade and sample and therefore reduce COGS.
`
`Feasibilitv: Will be determined following engineering evaluation ofbottle cleaning and
`pump placer equipment and all recommendations implemented to reduce the number of
`particulates associated with each packaging component associated with the trade product.
`
`Likelihood of Success: Moderate to high. Engineering and particulate issues must be
`resolved with the trade product.
`
`Time: 6-9 months following a successful feasibility study with the trade product.
`
`Cost: Milestones/Go no Go Decisions: ...
`
`Configuration Approved
`Successful Feasibility Study
`Analysis of 3 PV Batches
`Available for Launch
`
`FDA approval
`TBD
`TBD
`TBD
`
`Promotability: NA
`
`Market Forecast:
`
`- 5-
`
`HIGHLY CONFIDENTIAL-
`SUBJECT TO STIPULATED PROTECTIVE ORDER
`
`MEDA_APTX02875680
`
`PTX1006-00008
`
`8
`
`CIPLA LTD. EXHIBIT 2032 PAGE 8
`
`

`

`Product: ASTELIN NASAL SPRAY
`
`Project: Calmar-Albert Pump
`
`Objective: To qualify a backup vendor for the supply of pumps in an effort to reduce
`COGS.
`
`Background: Calmar-Albert has been working with operations to manufacture a pump
`that has comparable performance to the current Valois pump. After five years ofwork
`they have data to support further characterization of the pump (remaining tasks are
`outlined below) and may eventually be able to meet the current in vitro specifications.
`
`Feasibilitv: Moderate.
`
`Likelihood of Success: Moderate.
`
`Time: 18-24 months
`
`Cost: Milestones/Go no Go Decisions: ...
`
`Internal Resources (3 FTEs)
`Feasibility (In vitro/pilot stability)
`In Vitro Bioequivalence
`Full Stability
`Extractables
`FDA Submission
`FDA Approval
`
`2 years
`3 months
`6 months
`12 months
`3 months
`3 months
`6 months
`
`$795,000
`$179,520
`$486,000
`$950,000
`$183,000
`
`Promotability: None
`
`Market Forecast:
`
`- 6-
`
`HIGHLY CONFIDENTIAL-
`SUBJECT TO STIPULATED PROTECTIVE ORDER
`
`MEDA_APTX02875681
`
`PTX1006-00009
`
`9
`
`CIPLA LTD. EXHIBIT 2032 PAGE 9
`
`

`

`FORMULATIONS PROJECTS
`FORMULATIONS PROJECTS
`
`- 7-
`
`HIGHLY CONFIDENTIAL-
`HIGHLY CONFIDENTIAL -
`10
`SUBJECT TO STIPULATED PROTECTIVE ORDER
`SUBJECT TO STIPULATED PROTECTIVE ORDER
`
`MEDA_APTX02875682
`MEDA_APTX02875682
`
`PTX1006-00010
`
`CIPLA LTD. EXHIBIT 2032 PAGE 10
`
`PTX1006-00010
`
`10
`
`CIPLA LTD. EXHIBIT 2032 PAGE 10
`
`

`

`Product: ASTELIN NASAL SPRAY
`
`Project: Astelin/Steroid Combination
`
`Objective: To develop a patent-protected combination of Astelin and a corticosteroid as
`a nasal spray.
`
`Background: The technical aspects of developing this combination should be regarded
`as difficult Issues that will need to be addressed include: (1) Astelin is a solution,
`virtually all nasal steroids are suspensions; (2) Astelin is administered twice daily, most
`steroids are administered once daily; (3) there may be compatibility issues between
`azelastine and steroids. In addition, full clinical development is required, and indications
`(SAR, VMR, Nasal polyps, etc.) must be studied individually. Dose ranges of each
`component must also be explored, and each component must contribute significantly to
`the overall effect, i.e., the FDA "combination rule".
`
`Feasibilitv: Low
`
`Likelihood of Success: Low
`
`Time: After formulation development, full dose-ranging studies and clinical trials will
`need to be conducted. Depending on the indications sought, it is expected that at least 4
`to 5 years will be required prior to submission of an NDA, with approval approximately
`one year thereafter.
`
`Cost: Total development costs would likely be $75 to 100 million.
`
`Milestones/Go no Go Decisions: ...
`
`Milestone
`Formulation Development
`Clinical Development
`
`Time
`TBD
`TBD
`
`Cost
`TBD
`TBD
`
`Promotability: Advertising and promotion consistent with labeling.
`
`Market Forecast:
`
`- 8-
`
`HIGHLY CONFIDENTIAL-
`SUBJECT TO STIPULATED PROTECTIVE ORDER
`
`MEDA_APTX02875683
`
`PTX1006-00011
`
`11
`
`CIPLA LTD. EXHIBIT 2032 PAGE 11
`
`

`

`Product: ASTELIN NASAL SPRAY
`
`Project: Taste Masking-Meet Current Specifications
`
`Objective: To generate a product that has reduced bitter taste objections by simple
`modifications of the formulation.
`
`Background: The initial plan was to attempt minor modifications of the current
`formulation to mask the bitter taste and reduce objections. Numerous modifications were
`tried by PPD, however, all were either incompatible or resulted in significant changes to
`the in vitro specifications and will require extensive characterization and clinical studies.
`Hence, this short term fix is NOT feasible.
`
`Feasibilitv: NONE-all modifications will alter specifications requiring extensive
`characterization of product, per the current regulatory guidance, new FDA submission
`and clinical trials.
`
`Likelihood of Success: None
`
`Cost: Milestones/Go no Go Decisions: ...
`
`N/A
`Promotability: N/ A
`
`Market Forecast: N/A
`
`- 9-
`
`HIGHLY CONFIDENTIAL-
`SUBJECT TO STIPULATED PROTECTIVE ORDER
`
`MEDA_APTX02875684
`
`PTX1006-00012
`
`12
`
`CIPLA LTD. EXHIBIT 2032 PAGE 12
`
`

`

`Product: ASTELIN NASAL SPRAY
`
`Project: New Optimized Formulation
`
`Objective: To improve dosing and reduce objections (primarily taste) by increasing API
`concentration, increasing viscosity, and possibly by the addition of sweeteners.
`
`Background: Initial work indicated that any change to the current formulation results in
`what the guidance documents consider to be a major change and therefore require
`additional in vitro characterization, regulatory submissions and clinical trials for
`approval. Since any modification will follow this route to approval, the goal of this
`project is to create a formulation that is "optimal". The drivers are: (1) decrease bitter
`taste (increase viscosity, add sweeteners, decrease dose (increase concentration of
`active)); (2) evaluate once per day dosing; and (3) create barriers to competition by
`issuing a new and improved formulation.
`
`Feasibility: High. Technical aspects of formulation changes are achievable.
`
`Likelihood of Success: Cannot be predicted. Requires a taste panel to determine if the
`formulation changes produce the desired effect.
`
`Time: 3-4 years
`
`Cost: Milestones/Go no Go Decisions: ...
`
`Internal Resources
`Formulation Development
`Pump design/In Vitro Specs
`GMP Manufacture
`Clinicals
`FDA Submission
`
`Cost
`$795,000
`
`$1.2 M
`
`Time
`3 FTEs (2 years)
`3-6m
`18m
`TBD
`TBD
`TBD
`
`Promotability: Fully promotable, with the specific message dependent on the clinical
`data; however, this project would be successful if we could market a new and improved
`formulation with one spray per nostril BID dosing, and less bitter taste.
`
`Market Forecast:
`
`- 10-
`
`HIGHLY CONFIDENTIAL-
`SUBJECT TO STIPULATED PROTECTIVE ORDER
`
`MEDA_APTX02875685
`
`PTX1006-00013
`
`13
`
`CIPLA LTD. EXHIBIT 2032 PAGE 13
`
`

`

`CLINICAL PROGRAMS
`CLINICAL PROGRAMS
`
`-11-
`- 11-
`
`HIGHLY CONFIDENTIAL-
`HIGHLY CONFIDENTIAL -
`14
`SUBJECT TO STIPULATED PROTECTIVE ORDER
`SUBJECT TO STIPULATED PROTECTIVE ORDER
`
`MEDA_APTX02875686
`MEDA_APTX02875686
`
`PTX1006-00014
`
`CIPLA LTD. EXHIBIT 2032 PAGE 14
`
`PTX1006-00014
`
`14
`
`CIPLA LTD. EXHIBIT 2032 PAGE 14
`
`

`

`Product: ASTELIN NASAL SPRAY
`
`Project: One spray per nostril bid (Supplemental NDA)
`
`Objective: Conduct two, double-blind, placebo-controlled, efficacy and safety studies in patients with
`SAR to support a change to the dosage and administration of the product labeling to indicate that the
`recommended dosage for adults 12 years of age and older is one or two sprays per nostril twice daily.
`
`Background: Studies will be carried out by a CRO using investigators who are familiar with rhinitis
`protocols and) or who have participated in previous studies with azelastine nasal spray. Each study is three
`weeks in duration (l-week placebo run-in followed by a 2-week double-blind treatment period) and
`requires approximately 300 patients randomized to one of three treatment groups: (l) AzNS one
`spray/nostril bid, (2) AzNS two sprays/nostril bid, or (3) placebo nasal spray. Studies are conducted during
`the spring and fall allergy seasons using study designs that have been successfully implemented in previous
`company-sponsored investigations. Although no 2-week studies have been done in the U.S. with a one
`spray/nostril bid dosage regimen, this is the approved adult dosage in the EEC and there are several
`published double-blind, placebo- and comparative-controlled trials showing success with this dosage.
`
`Feasiblity: High. There are no foreseeable technical difficulties.
`
`Likelihood of Success: Moderate
`
`Time: Studies can be carried out over two successive allergy seasons (or could be conducted
`concurrently). Time from the beginning of protocol development to completion of a final study report is
`approximately 8 months for the first study. Lead-in time is approximately 3 months, which includes: (l)
`protocol and CRF development, (2) clinical packaging requirements, and (3) investigator recmitment,
`investigator documentation, and IRB approval. The remaining 5 months involve the (1) conduct ofthe
`trial, (2) analysis of data, and (3) preparation of study reports. Assuming the first study is begun in March
`2003 and has appositive outcome (final Clinical Study Report in July 2003), the Fall study can begin
`patient emollment in late AugusUearly September and be completed with a final report available during
`January 2004. Preparation of SNDA is 3 months with approximately 10 months for FDA review.
`
`Cost: Each study requires approximately 300 patients for statistical analysis. The cost is estimated as
`follows:
`Investigator Costs:
`CRO Cost:
`Clinical Packaging:
`EDC:
`TOTAL COST:
`
`$600,000.00 ($2000 per patient x 300 patients)
`$375,000.00
`$ 50,000.00
`$100,000.00
`$1,125,000.00 per study
`
`Milestones/Go no Go Decisions:
`
`Milestone
`Initiate First Clinical Trial
`Completion of first double blind Trial
`Final Clinical Study Report:
`If data is positive perform 2nd Trial:
`Completion of second DB Trial
`Final Clinical Study Report
`SNDA
`FDA review
`
`Timing
`March2003
`May 2003
`July 2003
`September 2003
`November 2003
`January 2004
`March 2004
`~January 2005
`
`Cost
`$1.125 million
`
`$1.125 million
`
`$266,700.00
`
`Promotability: Advertising and promotion, meetings and publications. The lower dosage option should
`reduce the incidence of taste problems associated with the two sprays per nostril bid regimen.
`
`Market Forecast:
`
`- 12-
`
`HIGHLY CONFIDENTIAL-
`SUBJECT TO STIPULATED PROTECTIVE ORDER
`
`MEDA_APTX02875687
`
`PTX1006-00015
`
`15
`
`CIPLA LTD. EXHIBIT 2032 PAGE 15
`
`

`

`Product: ASTELIN NASAL SPRAY
`
`Project: Perennial Allergic Rhinitis (Supplemental NDA)
`
`Objective: Conduct two double-blind, placebo-controlled, efficacy and safety studies to obtain an
`indication for the treatment of PAR in patients 12 years of age and older at a dosage of two sprays per
`nostril bid.
`
`Background: Studies will be carried out by a CRO using investigators who are familiar with rhinitis
`protocols and) or who have participated in previous studies with azelastine nasal spray. Each study is five
`weeks in duration (one week placebo run-in+ four weeks of double-blind medication), and requires
`approximately 200 patients randomized to treatment with either: (1) AzNS two sprays/nostril bid or (2)
`placebo nasal spray. These studies would be based on protocols from our previous clinical programs in
`SAR and VMR. Our previous successes in SAR and VMR suggest that azelastine would be an effective
`treatment for PAR without the need for a pilot study. Also, European studies have demonstrated efficacy in
`PAR at a dosage of one spray per nostril bid.
`
`Feasibility: High. There are no foreseeable technical difficulties in carrying out these studies.
`
`Likelihood of Success: Moderate
`
`Time: Studies can be carried out consecutively while avoiding the spring and fall allergy seasons. Time
`from the beginning of protocol development to completion of a final study report is approximately 8
`months for the first study. Lead-in time is approximately 3 months, which includes: (l) protocol and CRF
`development, (2) clinical packaging requirements, and (3) investigator recruitment, investigator
`documentation, and IRE approval. The remaining 5 months involve: (1) conduct of the trial, (2) analysis of
`data, and (3) preparation of study reports. Assuming that patient enrollment for the first study begins in
`February 2003 and the study has a successful outcome with a final report in June 2002, the second study
`can begin patient enrollment in November 2003 with a final report issued in March 2004. Preparation of
`SNDA is 3 to 6 months with approximately 10 months for FDA review.
`
`Cost: Each study requires approximately 200 patients for statistical analysis. The cost estimated as
`follows:
`Investigator Costs:
`CRO Costs:
`Clinical Packaging:
`EDC:
`
`$600,000.00 ($3000.00 per patient x 200 patients)
`$450,000.00
`$50,000.00
`$100,000.00
`
`TOTAL COST:
`
`$1,200,000.00 per study
`
`Milestones/Go no Go Decisions:
`Milestone
`Initiate First Clinical Trial
`Completion of first double blind Trial
`Final Clinical Study Report:
`If data is positive perform 2nd Trial:
`Completion of second double-blind trial:
`Final Clinical Study Report:
`SNDA
`FDA review
`
`Timing
`February 2003
`April2003
`June 2003
`November 2003
`January 2004
`March2004
`June 2004
`~April2005
`
`Cost
`$1.2 million
`
`$1.2 million
`
`$266,700.00
`
`Promotability: Advertising and promotion, meetings and publications. Labeling change will expand the
`use of Astelin to include patients with both indoor and outdoor allergies. Astelin will be the only second(cid:173)
`generation antihistamine with indications for SAR, PAR, and VMR.
`
`Market Forecast:
`
`- 13-
`
`HIGHLY CONFIDENTIAL-
`SUBJECT TO STIPULATED PROTECTIVE ORDER
`
`MEDA_APTX02875688
`
`PTX1006-00016
`
`16
`
`CIPLA LTD. EXHIBIT 2032 PAGE 16
`
`

`

`Product: ASTELIN NASAL SPRAY
`
`Project: Protocol 415 (Follow-on to Protocol 414 Claritin Failure Trial)
`
`Objective: Conduct a double-blind, placebo-controlled, efficacy and safety study to evaluate the effect of
`Astelin Nasal Spray monotherapy, Clarinex monotherapy, and Astelin plus Claritin combination therapy
`versus placebo in patients with SAR who have had an unsatisfactory response to Claritin. This study is the
`follow-on to Protocol414 and will be conducted according to an identical protocol.
`
`Bark!>round: Assuming a positive outcome in P414, the study will be carried out by a CRO using
`investigators who participated in P414, or who have participated in previous studies with azelastine nasal
`spray and are familiar with rhinitis protocols. The study will be conducted during the Spring 2003 allergy
`season. This study is three weeks in duration beginning with a one-week baseline screening period, (during
`which patients are treated with open-label Claritin) which is followed by a 2-week double-blind treatment
`period. The study requires approximately 400 patients randomized to treatment with either: (1) AzNS two
`sprays/nostril bid, (2) Clarinex 5 mg qd, (3) AzNS two sprays/nostril bid plus Claritin 10 mg qd, or (4)
`placebo nasal spray. (It would be possible to use the same study design and substitute Allergra for Claritin
`as the lead-in drug or Allegra for Clarinex as an active treatment arm.)
`
`Feasibility: High. There are no foreseeable technical difficulties in carrying out this study.
`
`Likelihood of Success: Moderate.
`
`Time: The study will be conducted during the Spring 2003 allergy season. Time from the beginning of
`protocol development to completion of a final study report is approximately 8 months. Lead-in time is
`approximately 3 months, which includes: (1) protocol and CRF development, (2) clinical packaging
`requirements, and (3) investigator recruitment, investigator documentation, and IRB approval. The
`remaining 5 months involve the ( 1) conduct of the trial, (2) analysis of data, and (3) preparation of study
`reports. Assuming that patient enrollment begins in March 2003 and ends in May 2003, a final clinical
`report can be issued in July 2003.
`
`Cost: The study requires approximately 400 patients for statistical analysis. The cost is estimated as
`follows:
`Investigator Costs:
`CRO Costs:
`Clinical Packaging:
`EDC:
`
`$800,000.00 ($2000 per patient x 400 patients)
`$650,000.00
`$250,000.00
`$200,000.00
`
`TOTAL COST: $1,900,000.00
`
`Milestones/Go no Go Decisions: ...
`
`Milestone
`Positive outcome of P414
`Initiate 2nd double-blind trial
`Final Clinical Study Report:
`
`Timing
`December 2002
`March2003
`July 2003
`
`$1.9 Million
`
`Promotahilitv: Advertising and promotion, meetings and publications. The two studies can be used to
`position Astelin as (1) the treatment of choice for patients who respond poorly to oral antihistamines and
`(2) as an alternative to intranasal steroids in these patients.
`
`Market Forecast:
`
`- 14-
`
`HIGHLY CONFIDENTIAL-
`SUBJECT TO STIPULATED PROTECTIVE ORDER
`
`MEDA_APTX02875689
`
`PTX1006-00017
`
`17
`
`CIPLA LTD. EXHIBIT 2032 PAGE 17
`
`

`

`Product: ASTELIN NASAL SPRAY
`
`Project: SAR and asthma
`
`Objective: Conduct a double-blind, placebo-controlled, efficacy and safety study to determine the effect
`of Astelin Nasal Spray 2 sprays per nostril bid on seasonal allergic rhinitis symptoms and the impact of that
`effect on asthma symptoms in patients with both SAR and asthma. Allergic rhinitis and asthma often
`coexist in the same patient. Because of the relationship between the upper and lower airway, in patients
`with both rhinitis and asthma, controlling symptoms of rhinitis may also have a positive impact on asthma
`symptoms.
`
`Background: Studies will be carried out by a CRO using investigators who are familiar with rhinitis
`protocols and/or who have participated in previous studies with azelastine nasal spray. The study can be
`conducted either during the Spring or the Fall allergy season using a protocol that was developed internally
`and reviewed by outside statistical and medical consultants. This study is three weeks in duration
`beginning with a one-week placebo lead-in period which is followed by a two-week double-blind treatment
`period. The study requires approximately 200 patients randomized to treatment with either: (1) AzNS two
`sprays/nostril bid or (2) placebo nasal spray.
`
`Feasibility: High. There are no foreseeable technical difficulties in carrying out these studies.
`
`Likelihood of Success: Low-to-moderate. A successful outcome depends on: (1) enrolling patients with a
`history of asthma exacerbations following exposure to seasonal allergens, (2) improving symptoms of SAR
`in these patients, and (3) the expectation that asthma symptoms will not worsen among patients treated with
`Astelin and will worsen among patients treated with placebo.
`
`Time: The study can be conducted during the Spring or Fall allergy season. Time from the beginning of
`protocol development to completion of a final study report is approximately 11 months. Lead-in time is
`approximately 3 months, which includes: (1) protocol and CRF development, (2) clinical packaging
`requirements, and (3) investigator recruitment, investigator documentation, and IRB approval. The
`remaining 8 months involve the ( 1) conduct of the trial, (2) analysis of data, and (3) preparation of study
`reports. Assuming that patient enrollment begins in March 2003 and ends in August 2003, a final report
`can be issued in October 2003.
`
`Cost: The study requires approximately 200 patients for statistical analysis. The cost is estimated as
`follows:
`Investigator Cost:
`CRO Cost:
`Clinical Packaging:
`EDC:
`
`$400,000.00 ($2000 per patient x 200 patients)
`$450,000.00
`$50,000.00
`$100,000.00
`
`TOTAL COST: $1,000,000.00
`
`Milestones/Go No Go Decisions
`
`Milestone
`Initiate Clinical Trial
`Completion of DB Trial
`Final Clinical Study Report
`
`Timing
`March 2003
`August 2003
`October 2003
`
`Cost
`$1.0 Million
`
`Promotability: Meetings and publications. Study is designed to position Astelin as the treatment of
`choice for SAR patients who also suffer from asthma. The study is consistent with positioning Astelin for
`specific types of rhinitis patients (85% of asthma patients also have allergic rhinitis).
`
`Market Forecast:
`
`- 15 -
`
`HIGHLY CONFIDENTIAL-
`SUBJECT TO STIPULATED PROTECTIVE ORDER
`
`MEDA_APTX02875690
`
`PTX1006-00018
`
`18
`
`CIPLA LTD. EXHIBIT 2032 PAGE 18
`
`

`

`Product: ASTELIN NASAL SPRAY
`
`Project: Somnolence/Cognitive Function Studies
`
`Objective: Conduct two double-blind, placebo-controlled, sleep latency (Multiple Sleep Latency Test)
`and/or cogniti