leveraging a comprehensive value creation platform to

© Copyright CMIC Group

Gaylord National Resort & Conference Center

April 11, 2019 – USA Washington

leveraging a comprehensive value creation platform to successfully enter and navigate the Japanese rare

disease market

2© Copyright CMIC Group

Foundation

1992

President/COO

Keiko Oishi

Capital

US$31 mil

Revenue

US$698 mil

7.0% up YOY

Employees

6,500+

Subsidiaries

22

Business Model

Pharmaceutical Value Creator

CMIC Overview


CMICʼs Unique Business Model (PVC)

CRO(Contract Research Organization)

CSO(Contract Sales Organization)

CDMO (Contract Development Manufacturing Organization)

Healthcare(Healthcare)

IPM(Innovative Pharma Model)

Sales and marketing support Business that enhancesindividual health value

Formulation development andmanufacturing support

Drug development support

Pharmaceutical company that existsfor the benefit of pharmaceuticalcompanies

Pharmaceutical Value CreatorStrategic partner for pharmaceutical companies


One-Stop Pharmaceutical Service

Sales & Marketing

Manufacturing

Approval

Clinical Studies

Non-clinical

Basic Research

CRO / CDMOPerform non-clinical studies

CROProvide support on clinical studies to pharmaceutical companies

SMO (Site Management Organization)Provide support on clinical studies to medical institutions and patients

Orphan PacificProvide support on drug development

CSO (Contract Sales Organization) Support sales & Marketing

HealthcareDrug information management and support for patients

CDMO (Contract

Development and Manufacturing Organization)Outsourced manufacturing of ethical and investigational drug

Orphan Pacific / CROMarket and sell drugsProvide and collect informationProvide support on PMSProvide support on clinical research

IPM (Innovative

Pharma Model)


A comprehensive support platform


The only CRO to help you reach market

●Development strategy

●PMDA Consultation on clinical studies

●Orphan Drug Designation

●Document preparation for clinical studies

●Conduct clinical studies

●Marketing License

●Manufacturing License

●CTD Preparation / NDA Filing

●Response to PMDA’s Inquiries

●Marketing Approval

●Listing of NHI Drug Price

Planning

Develop-ment

License

NDA

Marketing

Step 1

Step ２

Step３

Step ４


Delivering orphan drugs to rare disease patients

MarketingApproval

Development &Manufacturing

Distribution & Marketing

OrphanPacific

CollaborationCollaboration

MEDIPAL GroupCMIC Group

Investment/Founded

No.1 Wholesaler for Pharmaceutical products

Leading CRO in Japan

66% 34%

Innovative Pharma Model

Comprehensivesupport of the valuechain of pharmaceuticalcompanies

To thePatients

Non-clinicalStudies/Clinical

research

ClinicalStudies

Post-marketing surveillance /periodic safety update reports

Sales

C R O

SMO

Dru

g disco

very

Ap

pro

val app

lication

s

Gain

ing ap

pro

val

Dru

g laun

ch

Man

ufac-

turin

gIndustrial researchProvision of

medical information

ClinicalTrial

notific-ation

Re-examin-

ation

OrphanPacific

CDMO CSO

OrphanPacific

Local Pharmaceutical Companies

Overseas Pharm. Companies, not based in Japan

AcademiaBio-ventures

Fund ManagementCompanies

Service scope by OrphanPacific

http://www.google.co.jp/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=2ahUKEwiu5cXU75LaAhVKObwKHZLaCScQjRx6BAgAEAU&url=http://www.hanzomon-p.jp/service/strong/kigyo.html&psig=AOvVaw11iJrwx3X7BKxzEHqVPoan&ust=1522458913578482

http://www.google.co.jp/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=2ahUKEwiu5cXU75LaAhVKObwKHZLaCScQjRx6BAgAEAU&url=http://www.hanzomon-p.jp/service/strong/kigyo.html&psig=AOvVaw11iJrwx3X7BKxzEHqVPoan&ust=1522458913578482


Ultra-Orphan Drug(pts < 1,000)

Other Orphan Drug(pts 1,000- <50,000)

Approved Drugs 43 88

Already Approved in other countries outsideJapan

36 (84%) 63 (72%)

With Japanese clinical trialdata in Data package

35 (81%) 85 (97%)

Multinational Trial3 (7%)

Anticancer: 2

Metabolic: 1

11 (13%)Anticancer: 7

More than one RCT 24 (56%) 52 (59%)

RCT in Japan 3 (7%) 30 (34%)

Orphan Drug Development in Japan

Approved in January 2001 – December 2014: 131 Orphan Drugs

Maeda et al., Orphanet Journal of Rare Disease 2017; 12:143


Drug Lag Issue: Compared with the USA

3.1% 2.8%

9.3%

57.6%

15.2%

3.8%8.2%

EU

> 5yrs ahead

3-5 yrs ahead

1-3 yrs ahead

within 1 yr

1-3 yrs behind

3-5 yrs behind

>5 yrs behind

5.2%3.1%

3.1%

14.1%

22.5%

10.5%

41.4%

Japan

> 5yrs ahead

3-5 yrs ahead

1-3 yrs ahead

within 1 yr

1-3 yrs behind

3-5 yrs behind

>5 yrs behind

Murakami et al., Drug Discovery Today 2016; 23(4):544-549

In Japan, a half of Orphan Drug Designation (ODD) was completed 3 years or more behind the USA.


Standard schedule


Regulatory – PMDA Consultation

Pre-Consultation Official Consultation

Purpose Define scope of formal consultation items; however, sometimes more

Ask important questions to PMDA

Appointment 1-2 weeks in advance Two months in advance for drugs

Fees to Authority

Free Several million yen

Meeting Time 20-30 min (maybe longer) 2 hours

Minutes No official minutes Official minutes prepared by PMDA

Documents Briefing book (around 5-15 pages in total) including;

1) Product profile/ Company profile

2) Questions to be asked at the official meeting with sponsor’s position

3) List of documents to be brought to the official meeting

4) Timeline of the official consultation meeting

Documents: 20 copiesBriefing Book (Japanese)•General information of the product (background)•List of questions •Company’s opinion on questions with rationales/supporting data etc.

Attachments (Japanese in principle)•A part of US/EU documents (IND, IMPD, IB etc.)•Study Reports•Literature


Regulatory – PMDA Consultation Process

CMIC can support all processes


Regulatory – Clinical Trial Notification (CTN)

<Necessary components for initial CTN filing>– Application form （XML file, PDF file)– Management information (MS WORD file)– Attachments

- Protocol (Japanese)- IB (Japanese)- Template ICF for Japan (Japanese)- Scientific rationale (Japanese)- Template of CRF（Japanese）: as needed

<Necessary components for CTN amendment>– Application form （XML file, PDF file)– Management information (MS WORD file)– Attachments as required

CTNs for first dosing in Japanese require 30-day review.


Regulatory – CTN Process

Development of CTN

and attachments

Q&A (1)

Q&A (2)

Q&A (3)

Revision of CTN and

attachments based

on Q&As

Acceptance of CTN

(contracts with sites

can be executed)

ReplacementSubmission

PMDA

30 days

*: Q&As (inquiries from PMDA) normally comes in a week after CTN submission. Questions should be minimal if the protocol design has been agreed in the PMDA consultation.

CMIC can support all processes


General Regulatory Steps and Timeline in Japan

1st Month 2nd Month 3rd Month 4th Month 5th Month 6th Month 7th Month 8th Month

Data Gap Analysis

Strategy Development

Preliminary PMDA Consultation

Formal PMDA Consultation

Submission Meeting Minutes Finalization

1. Data Gap Analysis and Strategy Development2. Preliminary PMDA Consultation Meeting

(Quality, non-clinical study data, clinical study plan and protocol)3. Formal PMDA Consultation Meeting

(Quality, non-clinical study data, clinical study plan and protocol)

After finalization of meeting minutes⇒CTN submission for starting a clinical study


1. Japanese Patient Number Basically, number of patients must be < 50,000

If the disease is listed on MHLW’s Designated Intractable Disease, number of patients can be up to 0.1% of total Japanese population (127 million)

2. High Medical Need No other drugs or treatments are available, however

When alternative drugs or treatment are available, the superiority to existing drugs and treatments must be demonstrated with respect to efficacy and/or safety, or usefulness

3. High Probability of Development Success The theoretical ground for using the Investigational Products (IP) for the

target disease must be shown i.e., Preference of clinical data

The development plan must be realistic and be acceptable to the regulatory authorities i.e., Completion of PMDA consultation or CTN

Criteria for Orphan Drug Designation


Priority Review of MAA Documents‒ By the fast track review of NDA at PMDA, marketing approval can be

granted in 6-10 months

Longer Marketing Exclusivity Period‒ An exclusive marketing right for 10 years is granted

During this period, no generic drugs or bio-similar products can enter the market

Higher Drug Price‒ Higher NHI price for the drug can be given due to the addition of orphan

drug premium

Financial Support‒ Up to half of the drug development cost can be reimbursed for 3 years

NDA Fees‒ NDA fee for orphan designated drugs (23 mil JPY) is smaller than that of

non-orphan drugs (30 mil JPY)

Benefits of ODD to the Sponsor


1. Document preparation for pre-application consultation Prepare draft document required for ODD application

Apply for pre-filing consultation to MHLW

2. Pre-application consultation with MHLW Submit the draft documents to MHLW before the consultation meeting

‘Yes’ or ‘No’ for the application is suggested by MHLW

3. Application for ODD Submit the required documents for ODD application to MHLW

Answer inquires from MHLW

4. Designation Within 6 months after the application, ODD is granted by MHLW.

Procedures for ODD


Clinical Evidence of Efficacy and Safety in US / EU‒ If the Drug is already approved in US/EU, or clinical data on the drug are

available, there is a better chance to appeal for ODD application, although these are not mandatory

Timing of ODD Application‒ In the planning stage: Too early

‒ After PMDA Consultation: Possible / Negotiable

‒ After clinical trial notification: Best timing

Japan Representative Office for the Sponsor‒ For ODD application, Sponsor’s Japan office is not necessary

However, Japanese representative is needed to have close communication with MHLW/PMDA

‒ CMIC can play a representative role for Sponsor

Points to Consider for ODD Application

Just showing the development plan is not enough to get ODD. Required to show how committed you are in developing the product. So after CTN is best timing.

Not clearly written in guidance, but PMDA request the Japanese representative to be same as the company acting as ICCC, like CMIC. (Consulting firms without the ICCC capabilities are not applicable)


PMDA Consultation

ClinicalTrial

NotificationClinical Trials NDA

Timing of ODD Application

Pre-ODDConsultation With MHLW

Filing of ODD Application

ODD Approval


Standard ODD Timeline

MonthProcess

1 2 3 4 5 6 7 … 12

Assessment of

Medical Needs

Data Gap Analysis /

Development Plan

ODD Document Preparation

Pre-application Consultation with MHLW

Application for ODD

DesignationApproximately 6 months


Information to be included in ODD application:1. The number of patients, 2. Medical need for the drug, and 3. A concrete and realistic development plan

Information and data to be attached: 1. Background information on the discovery and the drug approval status

in other countries2. Manufacturing methods, specifications and testing methods3. Stability Data4. Pharmacological actions 5. Absorption, distribution, metabolism and excretion6. Toxicity data7. Clinical studies data

Application documents must be written in Japanese

ODD Application Documents


Scheme of AMAH & MAH

Foreign Pharma (MAH)

MHLWAMAH

Local Authorities

3. Application

4. Foreign Restricted Approval

2. Appointment of MAH in Japan as AMAH

1. License of Marketing Authorization Holder

Foreign Pharma

3. Application

2. Agreement between client and OP as MAH

Applicant

MAH

Foreign exceptional approval system(AMAH)

Marketing approval in Japan (MAH)

Marketing Approval System in Japan for foreign pharmaceutical companies

4. Approval

Applicant


J-NDA12 months

before J-NDA

1．You want to be in JapanMarketing Authorization Holder(MAH) OP becomes MAH for a product and submit J-NDA, negotiate NHI price, and also distribute and sell the product by OP.

2．You don’t want to be in JapanAppointed Marketing Authorization Holder(AMAH) A client appoints OP as a MAH in Japan and obtains “Foreign Restricted Approval”. On behalf of the client, OP submits J-NDA, negotiates NHI price, and also distribute and sell the product.

Review Period Launch

Approval

Drug price negotiationNHI price determination

Negotiation with Client

Options for Entering in Japan Market

When a foreign company plans to find a partner in Japan.Select from 2 options.


J-NDA submissionPreparation of CTD, communication/negotiation with the

authorities as an applicant or on behalf of a client.

Pre- launchTechnology transfer for acceptance test/release test.

Communication/negotiation with the authorities, including arrangement of GMP inspections.

Preparation for pharmacovigilance and post-marketing surveillance, including development of “Risk Management Plan”.

Preparation for quality control activities.

Preparation for supply chain management.

Services offered by OP(1)


Pre- launch Preparation for launch by Medical Affairs Dept., including compilation of

scientific/medical information, preparation of answers to medical inquiries from HCPs and providing MSL/MR training.

All other services necessary for the launch in Japan.

Post launch: All services necessary for maintaining the manufacturing and sales of the product

in Japan, including marketing, sales/distribution, and medical affaires, pharmacovigilance, PMS, quality assuarance and regulatory affaires activities.

Based on the GDP guidelines, logistics and distribution covered with a broad temperature range with various cold chain technologies in collaborating with the SP Line.

Japan office establishment All services necessary for establishing a Japan affiliate which can file an J-NDA

with a MAH license.

Services offered by OP(2)


Virtual Pharma Team

CMC Non-Cli/Clinical Project leader RA/PV

Project Management Contact/Negotiation

with PMDA Contact/Negotiation

with client

Project scheme for application/approvalwithin the CMIC Group

CTD preparation(M4,5)

Inquiry correspondence

with PMDA

Regulatory Submissions

CTD/Application Revision

RMP Development

PMS Plan

CTD preparation (M3)

Inquiry correspondencewith PMDA

GMP Inspection) Preparation for

Quality control(GQP)

http://www.cmic-holdings.co.jp/index.shtml

http://www.cmic-holdings.co.jp/index.shtml


Regulatory Consulting Experience (2014-2018)

ServicesNo. of project(2014-2018)

Planning Stage

Data Gap Analysis 74

Key Opinion Leader Interview 31

Regulatory Strategy Development 96

PMDA Consultation 78

Development Stage

Clinical Trial Notification (CTN) related actions as CRO 329

Preparation of CTN related actions as ICCC 97

Clinical Trial Protocol 108

Application for Approval Stage

Preparation of CTD 51

Response to Post-submission Inquiries 16

Strategy for NHI Price (Yakka) 25

Designation/Registration

“Sakigake” designation (New system started from 2016) 5

Orphan Drug Designation 13* 2008-2018

Japan Accepted Name (JAN) Registration 13*2008-2018

Drug Master File Registration 24

Foreign Manufacturer Accreditation 29

Application of generic drug (CMC) 8