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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

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IntroductionThis 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

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PCTA catheter market 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_catheters/angioplasty_products/prweb8853380.htm

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Goals and objectives for marketing the Cutter PTCA catheter device in Japano 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

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Development of Cutter catheter 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.

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FMA license application sites for Cutter catheter

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)

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General scope of classification and submission for PTCA catheter

1. PTCA catheter classification Class IV high risk device2. Is there a Standard? Yes, PTCA catheter approval

standard is 0401038 and JMDN code as

171840243. Is clinical supporting data

required? No4. Reviewed by who? PMDA5. Approval Timeline? 4 months

1. PTCA catheter classificationClass IV high risk device2. Is there a Standard? No3. Is clinical supporting data

required? Yes 4. Reviewed by who? PMDA5. Approval Timeline? 12 months

Classification With PAS Classification Without PAS

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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).

Cutter Catheter PTCA approval standard

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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)

Cutter Catheter PTCA approval standard

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Conclusion of comparison 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.

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Opportunities for faster Regulatory pathway

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.

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Opportunities for shorter pathway….

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.

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Milestones for registrationOption 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.

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Type of meetings with PMDA required

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)

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Available data for application

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.

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Missing technical information 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.

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Solutions to technical issues 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).

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QMS audits requirements (paper or onsite?) 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)

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QMS audit continued.. Product standard code (Seihin Hyoujun Sho)

documentation will be required for four sites-1. Framingham HQ 2. Springfield Cutter Catheter manufacturing site3. Distribution centers in Japan4. Distribution center in USA Meeting with PMDA for GMP consultation Submitting audit application form for

applicable sites Responding to audits.

20 Steps Cost (Yen) TimelineFMA 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 10,582Documents preparation Extra added cost During preparation of

documentsUser 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 and 5,176,582/ 51,765.82 (US dollars)=With clinical trial

Cost for registration

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Timeline for submission

FMA license application April-2011

FMA audit and approval

July 2011

Shonin Application preparationJuly 2011

Pre-submission meeting of regulatory pathway

August 2011Clinical trial evaluation

consultationSept-2011

Shonin application submissionSept -2011

Questions and response

to auditFeb-2012

2nd audit for Japan sitesJan -2012

Response to audit

Dec-2011

QMS audit 1st audit for US

sites Nov-2011

GMP audit meeting

Oct,-2011

Shonin Application QuestionsNov-2011

Responding to Questions Jan-2012

Senman Kyogi (SK)

Feb-April-2012

BukaiApril- May

2012Sashikae

May 2012

Final approvalJune 9th-

2012

Reimbursement application

June 10th-2012

Reimbursement approval-

July 2012

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Timeline as of March 2012 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)

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Expected Sales Japan Baverick and Cutter™ 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

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Financial and sales impact of Cutter catheter launch 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 2012.

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Questions?