This presentation discusses the regulatory strategy for obtaining approval of the Cutter PTCA dilation catheter in Japan. It outlines goals of obtaining the fastest approval as possible. Key steps include obtaining Foreign Manufacturer Accreditation licenses, preparing a submission dossier, conducting audits, and consulting with the PMDA. Challenges include missing technical data and non-compliance with some Japanese standards. Options to expedite approval include partial change application or pre-consultation meetings. The timeline aims for approval by June 2012 but risks delay depending on the pathway chosen and ability to resolve issues. Launch of the improved Cutter catheter could significantly increase sales and operating income for 2012.

1. REGULATORY STRATEGY
FOR PERCUTANEOUS
TRANSLUMINAL
CORONARY ANGIOPLASTY
(PTCA) DILATION
CATHETER FOR PMDA
(JAPAN) SUBMISSION
(DATED:12/7/2011)
Presented by Prajakta Buva and Pamela
Vacaflores
1

2. Introduction
2
This presentation will focus on:
 Goals and objectives for the key regulatory
submission for (Cutter) PTCA catheter in
Japan.
 Development history for the cutter catheter.
 Cost for the submission
 Timelines for the submission
 Risks to meet the proposed timelines
 Solutions

3. PCTA catheter market
3
 The global market for cardiovascular U.S. forecast is
to reach $1.84 billion by the year 2017.
 Factors driving growth in demand for PTCA products
include high incidence of coronary heart disease,
growing demand for minimally invasive procedures,
aging population, increasing obesity rates, and
technological advancements.
 PTCA market is highly concentrated and faces greater
competition because of the newest technology in
cardiac stents and lower re-imbursement costs in
Japan.
(Reference: New report by global Industry Analyst Inc.)
http://www.prweb.com/releases/PTCA_balloon_catheter
s/angioplasty_products/prweb8853380.htm

4. Goals and objectives for marketing the
Cutter PTCA catheter device in Japan
4
o Goal: The main goal is to obtain the fastest
approval for improved technology product Cutter
PTCA catheter in Japan.
o Objectives:
 Obtain MAH with valid license
 Submit a timely application and obtain approval
for
Foreign Manufacturer Accreditation-FMA (Japan
registration)
 Review of quality, efficacy an safety data of the
device product approval (Shonin application)
 Ensure QMS compliance surveillance

5. Development of Cutter catheter
5
 The Cutter catheter has been developed at a new
manufacturing site and sterilization site to have the following
“improved” characteristics:
1. Expanded indication to include dilatation of lesions from
previously implanted vein grafts.
2. New shaft material, diameter and changed tensile strength
specification and improved traceability.
3. Changed balloon material compliant with 10993 testing.
 This device was approved in Europe in July 2011 and pending
for approval by the FDA.
 Key step is to determine if the Cutter catheter is compliant with
all the sections (scope, reference standards, general
requirements) of the Japanese standard and ISO standards for
materials of available approval standard.


6. FMA license application sites for
Cutter catheter6
 The following sites will require preparation and
submission of applications to obtain an FMA
license:
 Neuco HQ and Distribution center (Framingham,
MA)
 Neuco Manufacturing site ( Springfield, MA)
 Gasex Corp, Sterilization site (Albany, NY)
o The following facilities will require FMA to have
completed submission for this application:
 Neuco Manufacturing site ( Springfield, MA)
 Gasex Corp, Sterilization site (Albany, NY)

7. General scope of classification and
submission for PTCA catheter
1. PTCA catheter classification
Class IV high risk device
2. Is there a Standard?
Yes, PTCA catheter approval
standard
is 0401038 and JMDN code as
17184024
3. Is clinical supporting data
required?
No
4. Reviewed by who?
PMDA
5. Approval Timeline?
4 months
1. PTCA catheter classification
Class IV high risk device
2. Is there a Standard?
No
3. Is clinical supporting data required?
Yes
4. Reviewed by who?
PMDA
5. Approval Timeline?
12 months
7
Classification With PAS Classification Without PAS

8. Intended use comparison with
approval standard.
 The Cutter™ PTCA
Dilatation Catheters are
indicated for balloon
dilatation of the stenotic
portion of a coronary
artery or bypass graft
stenosis for the
purpose of improving
myocardial perfusion
and for the post-
delivery expansion of
balloon expandable
stents
 The percutaneous
transluminal coronary
angioplasty catheters that are
used for dilation of constricted
coronary arteries and post-
dilation following stent
placement.
 This standard applies to
general type of angioplasty
balloon dilatation catheters
for coronary vessels (over the
wire, rapid exchange and
fixed wire).
8
Cutter Catheter PTCA approval standard

9. Tensile strength comparison
 Tensile strength with
catheter diameter
strength system is
for 2.1 mm diameter
it is 12 N (in-house
standard)
 For catheter
diameters greater >
1.85mm - 15N
(10555 standard)
9
Cutter Catheter PTCA approval standard

10. Conclusion of comparison
10
 Upon comparison, it was found that the Cutter
catheter has added scope for indication of use
(bypass graft stenosis) and does not meet tensile
strength specification as per standard. The
Shonin submission using the abbreviated
pathway (4 months) is not a straight forward step
for submission.
 Other options for submission include:
1. Submit a partial change application, since the
cutter catheter is improved from the previously
approved Baverik catheter device.
2. Submit a standard Shonin submission application
without approval standard and with or without
clinical trial data.

11. Opportunities for faster Regulatory
pathway11
Option 1:
 Pre-consultation meeting with the PMDA to determine if the Cutter
catheter meets the approval standard and if the results of the tensile
strength testing (as per 10555 standard) are in compliance with the
approval standard.
 Reason to push for a faster approval include:
 Neuco has similar approved device Baverick catheter with known
safety and efficacy profile.
 Changed raw material for balloon and catheter shaft passes
10993 standard biocompatibility testing.
 Cutter catheter has completed animal studies, bench testing and
clinical trials for expanded indication in the USA and have proved
safe and effective with excellent results.
 Submission review timeline with the approval standard is 4
months.
 Would save costs for the clinical trial consultation and the cost of
conducting clinical trials as per Japan standard or in Japan since
the application with the standard will not require clinical data.

12. Opportunities for shorter
pathway….12
Option 2
o To submit an application for a partial change (YAK 0216001) by pre-consultation
meeting with PMDA. This is a faster cost effective solution and will expedite the
approval saving 3-4 months due to the following reason:
 Partial changes will typically not go through Senmon Kyogi or Bukai, but will go
through Sashikai.
Cutter catheter application falls under the scope of partial change due to the following:
1. Expanding the indications of the Cutter™ PTCA catheter to include dilatation of
lesions inside of previously implanted artificial vein grafts results in a partial change.
2. Change in raw material for balloon and shaft catheter are minor changes.
Pitfalls of this application:
 A change requires submission and pre-approval from the PMDA before
implementation
 Pre-approval of changes may have deniel or delayed approval. This can be
resolved by clear communication between manufacturing sites and Japan and
implementing strategy for the necessity to manufacture and distribute the new
product.

13. Milestones for registration
13
Option 3- Shonin submission without approval standard would be the pathway for the
scope of this presentation which can be achieved by following steps-
 Obtain FMA license.
 Prepare and evaluate if all the Bio testing, sterilization compatibility results for raw
materials as per standards.
 Have as much as real time aging data stability study data ready.
 Prepare (STED) all the documentation for Shonin submission
 Prepare for QMS audits as per GMP Japan standard
 Clinical trial consultation with PMDA.
 Senman Kyogi (panel meetings for technical review) and Bukai review (world wide
safety data review)
 Sashikae
 Submit reimbursement approval as class C for common device which provides new
and unique function.
 Work closely with Japan team and PMDA.

14. Type of meetings with PMDA
required14
1. Clinical trial evaluation consultation to determine:
 Whether available data is sufficient to prove device is
safe
2. Pre-submission consultation to confirm:
 Regulatory pathway of a submission or the technical
development pathway
* This delays the submission by about 1 month;
however, it generally will eliminate 1 round of
questions from the regulators (2-3 months)

15. Available data for application
15
o Maximum data is available for Japan submission
which can help in expediting submission and
review process.
 All the design validation, sterilization validation
animal study, bench testing and bio- compatibility,
for raw materials as per ISO10993 is available.
 Clinical data will be required. Foreign clinical data
for 600 patients at 15 clinical sites in USA is
available.
 Real time aging stability data – 6 months data
completed on Nov, 2010 and 17 months data will
be available for the application on Sept, 2011.

16. Missing technical information
16
 Risk analysis and risk mitigation information a per JIST 14971
 Clinical trial data for new indication in compliance with Japan
GCP.
 Pre-approval submission data is not available for
implementing new changes in Japan.
 Tensile strength testing as per 10555, Japanese standard
data is not available.
 Product package insert indicates that the shelf life of Cutter™
PTCA Dilatation Catheter is 5 years from date of manufacture
but no 5 year real time aging data is available at the time of
submission.
 The type of catheter based on design is not clearly mentioned
in the packet insert, which is essential technical information.

17. Solutions to technical issues
17
Missing technical information issues can be
resolved cost effectively by:
 Indicating a minimum period of expiration date
(18 months) on the basis of available real time
aging data in package insert.
 Having clinical data compliant with Japan
GCP standard will save cost for conducting
clinical trials in Japan and will save approval
time.
 Performing tensile strength testing before
Shonin application as per Japan standard
(10555).

18. QMS audits requirements (paper or
onsite?)18
 QMS audits and compliance is an required step for any type of
approval including partial change application. Audits must be
completed before product approval.
 Requirements are similar to ISO13485.
 Additional status identification and product code information
required.
 Submission of pre-site audit documentation (in Japanese) will be
required.
Type of audits at each site will be:
 Framingham HQ and distribution center (paper audit)
 Labco testing lab (paper audit)
 Springfield Cutter Catheter manufacturing site (onsite audit)
 Gasex corp. Albany sterilization site (onsite audit)
 Distribution centers in Japan and in USA( paper audit)

19. QMS audit continued..
19
 Product standard code (Seihin Hyoujun Sho)
documentation will be required for four sites-
1. Framingham HQ
2. Springfield Cutter Catheter manufacturing site
3. Distribution centers in Japan
4. Distribution center in USA
 Meeting with PMDA for GMP consultation
 Submitting audit application form for applicable
sites
 Responding to audits.

20. 20
Steps Cost (Yen) Timeline
FMA license (1 paper Audit
and 2 site audits)
40,000+ 130000=
170,000
Within two week of application
QMS audits
1.Paper audits (3) 120,000 Within two week of application
2. Site audits (2) 130,000 (plus hotel and
airfare)
Pre- evaluation consultations
for clinical trials
8, 65, 200 Within 15 days after scheduling
meeting
Shonin submission 10,582
Documents preparation Extra added cost During preparation of documents
User fees 1,265,800 (no clinical trial,
3,846,800 (with clinical trial)
After application submission
Pre –submission consultation 34,000 Within 15 days after scheduling a
meeting
Total cost 2,595,582 /25,955.82 (US
dollars) = With no clinical trial
Cost for registration

21. Timeline for submission
21
FMA license
application
April-2011
FMA audit and
approval
July 2011
Shonin
Application
preparation
July 2011
Pre-submission
meeting of
regulatory
pathway
August 2011
Clinical trial
evaluation
consultation
Sept-2011
Shonin
application
submission
Sept -2011
Questions and
response to
audit
Feb-2012
2nd audit for
Japan sites
Jan -2012
Response to audit
Dec-2011
QMS audit 1st
audit for US
sites
Nov-2011
GMP audit
meeting
Oct,-2011
Shonin
Application
Questions
Nov-2011
Responding to
Questions
Jan-2012
Senman Kyogi
(SK)
Feb-April-2012
Bukai
April- May 2012
Sashikae
May 2012
Final approval
June 9th-2012
Reimbursement
application
June 10th-2012
Reimbursement
approval- July
2012

22. Timeline as of March 2012
22
 This submission could be regarded as standard Shonin
submission without approval standard and with clinical data
will take at least 12 months or longer and timeline won’t be
achieved. Clinical trial if required to be conducted in Japan
will require 3-4 months more. Time can be reduced by 1-2
months by:
 Submitting a QMS audit application with Shonin application
which can save time for submission by 1-2 months.
 Negotiating Bukai and Sashikae parallel can take off one
month of application which will be May or June ,2012 for
approval.
 This timeline will be achieved if approved by abbreviated
pathway-
1. Shonin submission with approval standard (4 months) or
2. Partial change application is accepted by PMDA (save 3-4
months)

23. Expected Sales Japan Baverick
and Cutter™23
 2011
• Sales Forecast: $11,900,000
• ASP: 980
• Gross Margins: 64.5%
• Operating Income $7,480,000
 2012
• Sales Forecast: $92,500,000
• ASP: 980
• Gross Margins: 62.0%
• Operating Income $57, 350,000

24. Financial and sales impact of
Cutter catheter launch24
 Introducing improved PTCA catheter with
excellent results, improved traceability and softer
and better approach in opening previously
implanted vein graft and will provide new and
better solution to improve therapy and reduce
patient burden. This will put Neuco corp. in strong
competitive position in the market.
 Sales will be less than expected 27.9% for year
2012.
 The operating income is expected to have 7-8 fold
increase for year 2012 will be less if Cutter
catheter gets approval in July 2012 and not March

25. Questions?
25