疫情后的药物临床开发战略

张丹 , MD, MPH

© 2020 ClinChoice – Confidential and All Rights Reserved

 主要内容

1 新政策

2 新环境

3 新园区

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A Sea Change in China Reverberating Globally

2015 2016 2017 2018

State Council Document 44: New Drug Definition ICH membership Unprecedented approvals
• Eliminated all MA backlogs • Global New • Initiate FIH trial & get first • Gardasil approval in 9 days!
via voluntary withdrawal approval in China! • 15 direct NDA approvals
(83% domestic withdraws Implications: • Roxadustat first approval in
for NDA) • Must file CN NDA before • Central Party Office & State China
• Established Green Channel MA approval anywhere else Council (Oct 8) ： Doc #42
• Required BE for all generics • Include Chinese sites in • 36 proposals
global trials • Summary of 2 year effort
• 19th National Party Conference
• Unsatisfied demand
• Demand for better Care

3
A Sea Change in China Reverberating Globally

2019 2020 2021 2022 and after

• “Urgent Medical Need” list US-China Trade Agreement (I) Post Election Politics: More Reforms
o First batch of 48 drugs; • Patent Linkage/Extension • Who will win?
2nd batch of 31 • Data Exclusivity • Does it matter? Reshape of global supply
o Summary of 2 year effort • Domestic manufacturing
oGlobal company Covid-19 Virus Pandemics
chain??
outperforms its local Covid-19 Pandemics: end/ ongoing?
competitors New US-China Relationship
o“4+7” Group Bidding More Reforms
oNew Drug Administration ICH E6- GCP (R2): July 1 2020 • Hainan Policy as a “free-trade”
Law island & special medical zone
Product Registration Policy • Great-Bay (Shenzhen) special zone
• Break-Through Designation • More ICH Implementations
• Accelerated Approvals
• Special Approvals 5G Implementation & Digitalization
• Impact on medical practice
DRG Implementation • Impact on biopharmaceutical R&D

Two Economic Cycles

• US Presidential Election

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ICH – 简介

INTERNATIONAL COUNCIL FOR HARMONISATION

Of Technical Requirements for Pharmaceuticals for Human Use

国际人用药品注册技术协调会


药审机构和工业界共同协调药物开发及审批技术标准


美国，欧盟和日本 共同建立于 1990


2015 年 10 月 23 日根据瑞士法律改组成非盈利性国际机构

扩宽会员

更多国际组织加入

改变决策过程

Source: ICH
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 Governance of ICH Association

16
Members
32
Observer
s

13 9 Members
Members and
and 2 1
Standing Standi
Observers ng
Observ
er

33 WGs
723
Experts

https://www.ich.org/page/organisation-ich
ICH 的产出（ 2019 年 11 月）

• Over 60 Guidelines on technical requirements on:

• Safety – 14 Guidelines
• Quality - 23 Guidelines
• Efficacy – 21 Guidelines
• Multidisciplinary - 6 Guidelines
• Electronic Standards for the Transfer of Regulatory Inform (ESTRI)
• CTD/eCTD
• MedDRA (standardised medical terminology)

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 Harmonised Regulatory
Guidelines
ICH Finalised Guidelines
Safety, Total = 14
▪ S1A – S1C: Carcinogenicity studies (3) ▪ S7A – S7B: Pharmacology studies (2)
▪ S2: Genotoxicity studies (1) ▪ S8: Immunotoxicology studies (1)
▪ S3A – S3B: Toxicokinetics and Pharmacokinetics (2) ▪ S9: Nonclinical evaluation for anticancer pharmaceuticals (1)
▪ S4: Toxicity Testing (1) ▪ S10: Photosafety evaluation (1)
▪ S5: Reproductive toxicology (1)
▪ S6: Biotechnology products (1)

Quality, Total = 23
▪ Q1A – Q1E: Stability (5)
▪ Q7: Good Manufacturing Practice (1)
▪ Q2: Analytical validation (1)
▪ Q8: Pharmaceutical development (1)
▪ Q3A – Q3D: Impurities (4)
▪ Q9: Quality risk management (1)
▪ Q4 – Q4B: Pharmacopoeias (1)
▪ Q10: Pharmaceutical quality system (1)
▪ Q5A – Q5E: Quality of biotechnology products (5)
▪ Q11: Development and manufacture of drug substances (1)
▪ Q6A – Q6B: Specifications (2)
Efficacy, Total = 21
▪ E1: Clinical safety (1) ▪ E12: Clinical evaluation by therapeutic category (1)
▪ E2A – E2F: Pharmacovigilance (5) ▪ E14: Clinical evaluation (1)
▪ E3: Clinical study reports (1) ▪ E15: Definitions in Pharmacogenomics (1)
▪ E4: Dose-response studies (1) ▪ E16: Qualification of Genomic Biomarkers (1)
▪ E5: Ethnic factors (1) ▪ E17: Multi-Regional Clinical Trials (1)
▪ E6: Good Clinical Practice (1) ▪ E18: Genomic Sampling (1)
▪ E7, E8, E9, E10, E11-E11A: Clinical Trials (5)
Multidisciplinary, Total = 6
▪ M3: Nonclinical safety studies (1) ▪ M7: Genotoxic impurities (1)
▪ M4, M4Q, M4S, M4E: CTD (4)
 ICH Other Products
Other products include electronic standards, a
standardized Medical dictionary, and Q&As.
Examples:
Safety
▪ S3A : Toxicokinetics and Pharmacokinetics (Q&As) ▪ S9: Nonclinical evaluation for anticancer pharmaceuticals
(Q&As)

Quality
▪ Q3D: Impurities (Training) ▪ Q7: Good Manufacturing Practice (Q&As)
▪ Q6A : Specifications (Decision Trees) ▪ Q8, Q9, Q10 - Q&As
▪ Q11: Development and manufacture of drug substances
(Q&As)

Efficacy
▪ E2B, E2C : Pharmacovigilance (Q&As, Specifications ▪ E7: CT in Geriatric Population (Q&As)
and related files, ESTRI) ▪ E14: Clinical evaluation (Q&As)
▪ E3: Clinical study reports (Q&As)
▪ E5: Ethnic factors (Q&As)

Multidisciplinary
▪ M1: MedDRA terminology & PtC ▪ M6: Gene Therapy (Considerations)
▪ M2: Electronic standards (Recommendations - ESTRI) ▪ M8: eCTD
▪ M3: Nonclinical safety studies (Q&As)
 Membership in the Assembly Eligibility
Criteria for Regulators

• Engagement in the ICH Process

o Past regular attendance in at least 3 ICH meetings during the
previous 2 consecutive years.
o Past appointment of experts in at least 2 WGs.
• Application of ICH Guidelines
o Having implemented at least the following ICH Guidelines
upon application for Membership:
- Q1: Stability Testing Guidelines
- Q7: Good Manufacturing Practice Guide for Active
Pharmaceutical Ingredients
- E6: Good Clinical Practice Guideline

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 Membership in the Assembly
Eligibility Criteria for Industry

• Type of Organisation
o Be a global pharmaceutical industry association representing
a global constituency.
• Engagement in the ICH Process
o Past regular attendance (as former ICH Interested Party or
Observer) in at least 3 ICH meetings during the previous 2
consecutive years.
o Past appointment of experts in at least 2 WGs.
• Impact of ICH Guidelines
o The Association and/or its members must be regulated or
affected by ICH Guidelines.
 ICH Assembly Members

• Each Member may appoint up to 2 Representatives.

• As of November 2019, there are 16 ICH Members:
o Founding Members:
▪ Founding Regulatory Members: EC, Europe; MHLW/PMDA, Japan;
FDA, United States
▪ Founding Industry Members: EFPIA; JPMA; PhRMA
o Standing Regulatory Members: Health Canada, Canada;
Swissmedic, Switzerland
o Regulatory Members: ANVISA, Brazil; HSA, Singapore; MFDS,
Republic of Korea; NMPA, China; TFDA, Chinese Taipei
o Industry Members: BIO; IGBA; WSMI

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 ICH Observers
• Limited eligibility criteria for Observers. No duties are imposed.
• Observers have the right to attend ICH Assembly meetings but no right to vote and
no automatic right to appoint experts in WG. Former observers in the Steering
Committee (WHO and IFPMA) are Standing Observers in the Assembly, maintaining
their right to appoint experts in WGs.
• As of November 2019, there are 32 Observers:
✓ Standing Observers: IFPMA; WHO
✓ Legislative Authorities: ANMAT, Argentina; CDSCO, India; CECMED, Cuba;
COFEPRIS, Mexico; CPED, Israel; INVIMA, Colombia; JFDA, Jordan; MMDA,
Moldova; National Center, Kazakhstan; NPRA, Malaysia; NRA, Iran;
Roszdravnadzor, Russia; SAHPRA, South Africa; SCDMTE, Armenia; SFDA, Saudi
Arabia; TGA, Australia; TITCK, Turkey
✓ Regional Harmonisation Initiatives: APEC; ASEAN; EAC; GHC; PANDRH; SADC
✓ International Pharmaceutical Industry Organisation: APIC
✓ International Organisations regulated or affected by ICH Guideline(s): Bill and
Melinda Gates Foundation; CIOMS; EDQM; IPEC; PIC/S; USP 21
https://www.ich.org/page/members-observer
 Overview of the participation of current
Members and Observers in ICH

723 Experts in 32 WGs– as of 14 October

2019

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ICH – 运行目的

Promotion of public health through international

harmonization that contributes to:


Prevention of unnecessary duplication of clinical trials and post
market clinical evaluations

Development and manufacturing of new medicines

Registration and supervision of new medicines

Reduction of unnecessary animal testing without compromising
safety and effectiveness

Accomplished through Technical Guidelines that

are implemented by the regulatory authorities.

Source: ICH
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ICH 的冲击


ICH 技术指南 - 国际药品注册领域的核心规则

国际协调，统一成员国之间注册技术要求，

避免浪费人力、财力、物力，

减少病人风险

促成新药研发数据和注册的国际互认”

- 利好国际药企（ MNC ）在中国做 MRCT

- 看好中国市场 - 重回中国 : Merck 90% sales increase in Q3 2019

- 激励中国的创新药走向世界 -- 必由之路：
- “4+7” 带量采购 +DRG ：仿制药向创新药转型更具挑战性
- 商业保险有待进一步提高（ 30% in USA vs 2%-7% in China)
- 目前只有一个中国的新药作为成药进入 ICH 国家 / 地区（百济神州）

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NMPA NDA Approvals after ICH

Total for 2019 : 51 products approved for NDA, but only

nine from domestic firms
©Silk Road Life Sciences, Inc. 17
NDA Application From “Domestic” Firm

I 类药 : Complete NDA
百济神州：泽布替尼
和记黄埔：呋喹替尼获批的临床适应症为转移性结直肠癌
Fibrogen: 肾性贫血药物
中国在全球首先批准
US FDA and EMA: pending-cardiac safety
桂林制药：青蒿素治疗抗药的疟疾
砒霜治疗白血病
II 类药： 505 （ b2 ）
固定配比联合用药：马来酸依那普利叶酸片
PD1 扩大新指证
仿制药： ANDA

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ICH 神户及夏略特大会 : ICH Guideline

E8(R1) EWG: Revision on General Considerations for Clinical Trials (Rapporteur: Dr. LaVange – FDA,
US; Regulatory Chair: Dr. Sweeney – EC, Europe)
The E8 Guideline has high level descriptions of trial objectives and design, but
does not address how design or planning considerations can optimize trial and
data quality. The set of trial designs described in E8 is limited and does not
reflect the range of designs in use today. To resolve these issues, E8(R1) will:
1) identify a basic set of critical-to-quality factors (e.g. eligibility criteria,
masking, types of controls, outcome ascertainment, site feasibility, safety
monitoring, statistical analysis, and investigational product handling and
administration) that can be adapted to different types of trials to support
the meaningfulness and reliability of trial results and to protect human
subjects.
2) address a broader range of trial designs and data sources.
3) provide an updated comprehensive guide to, or cross-referencing of, all
other relevant ICH guidelines that inform the design, planning and conduct
of clinical research, without reproducing the detailed material found in
those guidelines.
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ICH 2019 阿姆斯特丹大会

会前活动 public consultation (Step 2b of the ICH process)

Optimization of Safety Data Collection (E19) in April 2019;
Revision on General Considerations for Clinical Trials (E8(R1)) in May 2019.
Four new Regulatory Observers: ANMAT, Argentina; CPED, Israel; JFDA, Jordan and
SFDA, Saudi Arabia
Progress on existing ICH guidelines
Revised E2B(R3) Question & Answer (Q&A) regarding Implementation:
Transmission of Individual Case Safety Reports
Implementation of ICH guidelines
E17 guideline: 6 training modules and one video

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ICH 2019 阿姆斯特丹大会

Agreement on new ICH harmonization activities

E6(R3) Guideline for Good Clinical Practice, which is proposed to revise the
existing ICH E6(R2) Guideline to address the increasing diversity of study types
and data sources that are being employed to support regulatory and other
health policy decisions in line with the ICH Reflection Paper on GCP Renovation.
E2D(R1) Post Approval Safety Data Management: Definition and Standards for
Expedited Reporting, which is proposed to update the existing ICH E2D
Guideline to incorporate pragmatic potentially risk-based approaches of the
management of information from existing and any new data sources, to enable a
greater focus on the data sources that will optimize signal detection activities
and public health.

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ICH 2019 阿姆斯特丹大会

Global ICH Public Stakeholder Meeting

ICH E8 Guideline Revision on General Considerations for Clinical Trials (reached
Step 2b of the ICH process)
Meeting on 31 October 2019 at Silver Spring, MD, USA, will discuss planned
next steps for the guideline’s development and its role in ICH’s Good Clinical
Practice (GCP) Renovation
Another meeting will take place in Tokyo, Japan on 25 July 2019.

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ICH GCP Renovation

GCP Renovation: Modernization of ICH E8 and Subsequent

Renovation of ICH E6
1) E6 (R2) Addendum （ Mar 2018 by FDA ）
1) Sponsor ： Risk-based Monitoring, central & remote monitoring

2) EDC & system validation; certified copy

3) Investigator is responsible for the qualification of all people involved

4) Sponsor: Quality Management system with risk-based approach

5) Sponsor: CROs & other service providers

6) Sponsor: EDC SOP & validation

7) Sponsor: Monitoring plan

2) E8 (R1): ICH 2018-Quality By Design Concept 23

ICH E-series: Next Step
GCP Renovation: Modernization of ICH E8 and Subsequent Renovation of ICH E6
3) E6 Renovation: anticipate and address a broader range of study types and
data sources, while retaining the current E6 focus on good clinical
investigative site practices.

Annex 1: Traditional Interventional Trials of unapproved or approved drugs:

risk-based approach

Annex 2: Non-Traditional Interventional Trials and/or data sources: real

world data

Annex 3: Non-Traditional Trial Designs. designs other than RCTs and may
include observational studies, patient registries, and other non-traditional
trial designs that rely heavily on alternative data sources (e.g., EHRs, claims
data, etc.)

Implementation of ICH E17 MRCT guidelines (Separate Slides) 24

ICH GCP Renovation: Implication
GCP Renovation: Modernization of ICH E8 and Subsequent Renovation of ICH E6

1) Principle Investigator
 Study Team

1) Qualification of Co-PI and Sub-I

2) Training & Record

3) Supporting Team

2) GCP center

1) Qualification of IT system

2) Safety reporting

3) CRO

1) Qualification of the sites

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2) Monitoring plan for the site, including training record
ICH 2019 Singapore Conference

ICH E6 (R3) Kick-Off

Dr. Guodong Fang, CMO of FMD, is a member
Academic KOL and patient inputs
ICH E19 Ongoing
EU feedback: safety data from pre-NDA trials
ICH E20 Kick-Off
Adaptive Design
ICH E2(D) R2
Concept paper

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中国加入 ICH 后的行动

Implementation of E17 MRCT guideline

ICH E17 MRCT guideline was approved by ICH in Nov 2017
CFDA organized its discussion forum in January 2018
ICH formed implementation committee
Implementation of M4 （申报格式）
Implementation of M8 （电子申报）
Implementation of E2A, E2B, E2D, and M1 ( 药物安全性 )
Implementation of 29 ICH guideline on Jan 1, 2020

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环境变化过程中的 PV 系统

新及老系统的交替
66 号局令（ 2018 年）上市许可持有人必须汇报所有的 AE
上市后 PV 重点监测：必须在真实世界条件下进行
英文 - 中文
First in English, but has to be translated into Chinese within 15 days of initial reporting
E2B (R2) vs E2B (R3)
From May 1 2018 to May 1 2019
CDE vs ADR
CDE 处理 NDA 批准中的强制性条件
ADR 处理上市后的 PV 重点监测
发生在海外的 AE 及 SAE
如果在国内正在进行新指症临床
向 CDE and ADR 同时申报

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ICH 发起国的审评政策及变化

USA: Innovation leadership & Cost-control

Real-time NDA application & approval for oncology products
Seamless trials
Phase I + Expansion Cohort
Real-world data to support drug applications
Adaptive design for pivotal trials
Expansion of the scope of 505 B(2)
Model protocol: GBM
“Right-to-Try” Act
Hatch & Waximan Act 1984
Biosimilar & “Interchangability”
Orphan drug policy: a dominant play
Acceptance of Clinical Data from China

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ICH 环境下的中美比较
美国的优势
Innovative R&D is abundant due to consistent investment on basic research and development
Talents are abundant and complete
Education system favors innovation and development both
Best regulatory system in the world
Sophisticated investment environment for biotech/device
VC/PE/IPO
Best reimbursement system for biotech/device/diagnostics
Commercial & government insurances are immediately available
Experienced study sites
PIs are well qualified with professional team available
Industry-friendly
Experienced CROs
Almost all biggest ones are in USA
美国的劣势
No more patients
Enrollment too slow
High costs 30
ICH 环境下的中美比较
中国的优势
Has the world largest patient population
Treatment naïve population
Rare in USA but not rare in China
Has lower total costs
Patient costs is significantly lower
CRO fees is lower
Government support
Lower upfront costs
Expanding pharmaceutical market: bright future?

中国的劣势
Lack of talents who has NCE global development experience
Senior executive: rare more than panda
Middle level managers: better in Taiwan
Entry-Level: high turnover
PIs are not experienced enough to meet ICH technical requirement
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FDA Inspection in China
Successful examples
Sanofi (COMMIT Trial) led by Fu-Wai Hospital for Coronary Heart Syndrome
Total enrollment: 45,000 patients from 500 sites in 4.5 years
Primary end-point: OS
US Inspection team went to FU-Wai Hospital and local community hospital
Obtain NDA approval with this single pivotal trial
Many Oncology Trials
Unsuccessful case
BMS global phase III pivotal Coronary Heart Syndrome trial
8 sites in Shanghai were disqualified
Major Findings:
Sharing of EDC accounts
Patients were managed by non-registered physicians
NDA filing was delayed by 9 months

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 GCP ， Pivotal Trial & NDA

USA China
Pivotal Trial Definition Adequate & well controlled Western medicine vs TCM
# of Pivotal Trials 2 (1 for Orphan or Unmet Need) 1
Adaptive Design Accepted for pivotal trial Case by case
Safety Sample Size for Pivotal Large Small
Cardiac & liver Toxicity Trial required Case by case
Non-NDA approval for Human Use EUA & Compassionate Use Compassionate Use
IIT (Investigator Initiated Trial) Supporting Evidence Supporting or Pivotal
RWD & RWE for NDA Accepted with one NDA approval Guideline issued
ICH GCP ICH E6 （ R2 ） 2016 ICH E6 （ R1 ）： 1995 ， R2 ， 2020
NDA timeline PDUFA ： guaranteed Various

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 IND in USA vs. CHINA

USA China
Pre-IND Meeting Optional Almost Mandatory for New Products
IRB & IND Simultaneously Sequential
IND for IIT FDA NMPA and Other Government agencies
CDP Yes Mandatory
eFiling Yes No
Timeline 30 days 60 working days
Orphan Designation Yes Yes, but limited
IND filling fee Zero Increased
Meeting Minutes FDA produces Sponsor generates first draft
Selection of PI Less impact Significant Impact on IND decision

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 Conducting Clinical Trials in US vs. China

USA China
Protocol Design Capability Abundant Rare
PI More, experienced Less experienced
Sites Any place GCP sites (~700)
IRB Local & Central Local Only
Genome Protection CIFUS? Yes
HIPAA Yes No
Patient Pool Less than trial needed Large & concentrated
Patient Quality Less treatment naive Treatment naive
Cost High 1/3 ~ 1/4 US cost
Quality for MRCT Good Excellent
Quality for Local trial Good Very Poor
CRO availability Excellent Excellent
CRO sophistication Excellent Most are inadequate

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 Conducting Clinical Trials in US vs. China

USA China
Scientific Committee Yes Almost None
Central Lab Yes Yes
Biomarker test Yes Yes, academic center
Biologic samples Transfer to other countries Need approval for going out
Safety Handling ICH E2 & M1 Started May 2018 & need more training
Concomitant drug Pre-determined Contamination of herbals
SMO Support Optional Almost Mandatory
Lasagna Law Applicable Applicable
Access to patients Multiple sites More concentrated
Language requirement English Chinese
Government Inspection NDA or for cause Mainly NDA triggered
Acceptance of foreign data Yes Yes, oncology & rare indication
Turnover of employees Minor to moderate High in Shanghai & Beijing

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Regulatory Strategy: US vs China

 Special treatment in the Era of COVID-19 Pandemic Diseases

 US:
Compassionate Use (expanded access)
EUA (emergency use authorization)
CTAP (Coronavirus Therapy Acceleration Program)
New guidelines
FDA Guidance on Conduct of Clinical Trials of Medical
Products during COVID-19 Public Health Emergency
Other product specific guidelines
 China
Special review and approval pathway
IIT and IST approaches, TCM operation
New guidelines
NMPA Guidance on Conduct of Clinical Trials of Medical
Products during COVID-19 Public Health Emergency: role of
DSMB
New GCP guidelines: critically important
Treatment guidelines
 Trial Design for the COVID-19 Pneumonia
 Global vs local
 Rigorous vs observational
 Double blind vs open label
 Two or more arms vs single arm
 Pivotal vs POC
 ICH E6 GCP R2 vs R1
 Adaptive vs. fixed design
 Ongoing ICH E20
 Why adaptive?
 The role of DSMB/IDMC
Clinical trial: Global vs Local
 Optional or only way to go?
 COVID-19 Pneumonia trials: chasing patients
 Other non COVID-19 trials:
 Access to the patients
 Implementation of the trials
 Global regulatory strategy
 How to initiate the global trial
 In-house team
 Working with a CRO
 Financing consideration
 Partnership consideration
Global Collaboration in the Era of COVID-19
 Global Partnership:
 BD
 License-in and license-out
 Obtain help from other third-party: Silk-Road Company
 Working with government agencies, NGO and WHO
 Global clinical operation
 Working with a CRO
 Global Fund-raising
 VC/PE
 Foundation
 Government
 China-US, China-EU and China-Japan collaboration?
Adaptation of New Technologies
 Digitalization
 ICH E6 GCP (R2)
 Remote monitoring
 Risk-based monitoring
 Define and measure the risk(s)
 Decentralization
 Home-based or individual-based approach
 Qualified equipment
 Regional or central IRB
 Real-world data
 How to clean the data
 How to analyze the data properly
 How to protect privacy
New Regulatory Environment
 Implementation of ICH E6 (R2)-GCP 第二版
E6 (R2) Addendum （ Mar 2018 by FDA ， July 1 2020 by NMPA ）
1) Sponsor ： Risk-based Monitoring, central & remote monitoring
2) EDC & system validation; certified copy
3) Investigator is responsible for the qualification of all people involved
4) Sponsor: Quality Management system with risk-based approach
5) Sponsor: CROs & other service providers
6) Sponsor: EDC SOP & validation
7) Sponsor: Monitoring plan
8) Informed Consent for study subject with disadvantages
9) Registration of GCP centers
New Regulatory Environment
 New guidelines for
 Review procedure for Breakthrough designation
 Procedure for Priority Review
 Conditional approval
 MAH outside of China
 Data Exclusivity
 New patent law
 Patent linkage
 Patent compensation
 China-US Trade-Agreement (Part I)
New Reimbursement Environment
 Government Insurance Scheme ( 医保局）
 Extended “4+7”tendering system
 Generics
 “me-too”
 New drug?
 Implementation of DRGs
 30 cities
 More cities to follow?
 Commercial Health Insurance
 Medi-Gap?
What is the best practice after COVID-19 Pandemics?

 Global Strategy
 Still there?
US-China relationship
 Where will the patients come from?
COVID-19 Patients?
 ICH movement
Still coming strong
Regulatory asymmetry still applies
 Reimbursement consideration
US vs China
 Discovery-development-commercialization
US-China dual play
 ICH BioPark: need a new type of biopark which supports global strategy
ICH BioPark

Adapt ICH guidelines to

Assess biopark projects to make sure it meets ICH standard
All projects can expand into global market
Design relevant policies to support global operation of companies
Talent policies
Global trial policies
Global Fund raising and IPO policies
Global Reimbursement policies
Super Incubator
Support global talent search
Support global R&D & MAH efforts
Support global BD activities
Support global patent strategy
Goal: entry into global market
Adaptation of New Technologies and Methods

Adaptive Design (E20) adds 13% more NDA successful rate in US FDA
ICH E20 EWG started in Nov 15 2019 in ICH Singapore Conference
Patient-centered trial design adds additional 19% NDA successful rate in US FDA
New guideline from US FDA
Precision Medicine (biomarker) design adds 10% more NDA successful rate in US FDA
Companion test guideline from US FDA
Adapting Real-world data would add additional 21% more NDA successful rate in US FDA
New guideline from US FDA
ICH E6 (R3) EWG started in Nov 15, 2019 in ICH Singapore Conference

Confidential 47
US-China Development Strategy in the Era of ICH
Discovery in USA
Early phase development: US-China combined to avoid bridging-trial in later phase
Late phase development: majority from China enrollment
Regulatory System: US + China
NDA: both countries and also going to other ICH countries
China NDA first strategy for global unmet medical need: only one pivotal trial needed
US NDA first strategy: Orphan indication and Oncology Indications
Following E17 MRCH guideline for global and regional trials
Ethnical difference
Standard of Care
Manufacture: MAH, lower cost in China (Economy of Scale)
Commercialization: USA and then China
Government insurance vs. commercial insurance
IPO
Mainland China
Hong Kong
USA 48
发展历程

在全球法规能力的加强和医学能力的
5月 加强 10 月
7月
方恩北京公司成立 Q1 获得 D 轮融资
上海分公司成立 成为国际一知名大药厂中国外包主要合 沈阳办公室设立
作伙伴 高盛领头，礼来亚洲基金跟头
Q2
2009
2008 8月 武汉办公室设立
2007 2010
10 月
2011 南京办公室设立
10 月 收购 iMED Global 公司（成立于美国， 2019
是一家国际化 CRO 公司）
11 月 台湾办公室设立 5月
5月 2012
方恩天津公司成立 成都办公室设立 2018
成为 CDISC 认证 方恩与 K&L 公司（ 1995 年成
金牌会员 2013
12 月 立于美国）合并，成立 FMD
2016
方恩香港公司成立 K&L 海外 2014
2015
6月
分公司 8月
广州分公司成立
韩国办公室设立 1月 石家庄分公司成立
成为 Oracle InForm
成为 Medidata 亚美尼亚办公室设立、
认证合作伙伴
认证合作伙伴
Q4

日本办公室设立

49
FMD Global Service, Global Clients
China
• Clinical Operations
Armenia • Biometrics
• Medical Affairs • Medical Writing
• Pharmacovigilance • Clinical Safety
• Regulatory Operations • Regulatory Affairs
• Clinical Operations
• Statistical Analysis
• Clinical Data Management
United States
• Biostatistics/Programming
• Clinical Data Management
• Regulatory Affairs
• Pharmacovigilance Philippines
• Pharmacovigilance
• Medical Affairs
India • Medical Writing
• Pharmacovigilance • Biostatistics
• Regulatory Affairs & Ops • Clinical Data Management
• Toxicology • Regulatory Affairs
• Technology & Consulting
• Statistical Analysis

1700+ Employees 20 Offices 55 Cities

方恩公司概况

>25 ~1700 >700

员工覆盖 8 个国家 55 个城市
公司发展历程超过 25 年，国内临床经验 中国：北京、沈阳、上海、天津、 南京、广州、成都、武汉、石家庄、香港 、台湾 完成了 700 多个 1-4 期药物 / 器械研究
13 年 海外：美国、英国、亚美尼亚、日本、韩 国、印度、菲律宾

>150 >300 >1000

中国 NMPA 及美国 FDA NDA 及 和国内超过 300 家 GCP 研究中心取得 和国内超过 1000 位研究者建立合作
IND 递交超 150 个 合作

>500 >350 > 250

生物统计，编程和数据管理专家建立专业化 中国、印度、欧洲和美国安全和医学写作专 SMO 公司，经验丰富的项目经
数统平台 业人员支持安全审查和监管 理， CRC 可覆盖覆盖中国的 300 个医
院
51
方恩医药在中国 CRO 市场地位
中国临床外包市场
($ bn)
12-17 17-21E
8.4 CAGR CAGR
6.8 24% 23%
中国临床研发 临床服务外包增长率 5.6 3.2
中国临床外包增长率 4.5 2.7
投入增长 2012 23% 3.6 20% 19%
2012-17 CAGR 24% 2.8 2.4
2012-17 CAGR 20% 2017 27% 1.8 2.2 1.9
2017-21E CAGR 23% 1.3 1.4 0.8 1.0 1.6 5.2
2017-21E CAGR 19% 2021 31% 0.6 0.7 1.3 3.3 4.1
(26% for clinical) 1.6 2.1 2.6 27% 26%
0.6 0.8 1.0 1.2

2012

2013

2014

2015

2016

2017

2018E

2019E

2020E

2021E
Clinical Preclinical

2017 年中国临床外包市场份额占比 方恩医药在中国临床外包市场中，因为创新型和国际化，占据优势地位

​IQVIA
12% Leading Global
​ &G
R ​Paraxel (32%)
Pharma #2
6%
2%
​Covance
6%
​ClinPlus
​Other ​INC/InVentiv
1%
46% 3%
​Rundong ​ICON/PPD/PRA etc.
1% ​Boji 6%

1% ​TigerMed
​Xingaofeng 12%
1% CTS Leading Domestic
0.3% (21%)

​FMD
3%

• Source: Annual filings; CenterWatch; Wanlian Securities

Integrated Service Throughout Drug Lifecycle
Clinical Operations

Medical Writing Medical Translation

Regulatory Strategy & Operations Drug Safety/Pharmacovigilance

Medical Strategy Data Management

Third Party Audit Site Management

Biostatistics

IND Phase 1 Phase 2 Phase 3 NDA Phase 4

方恩品质 – 临床研究治疗领域
 参与了 85 个创新药的临床研发与注册申报，承接了 720+ 临床试验

300
279

项目分期划分
250

200

150

100
72
60
50 42 40 34
26 25 21 21 20 19 17 17 15 14 14 13 10 9
2
0
肿瘤 内分泌 心血管 抗感染 呼吸 眼科 血液 骨科 精神 免疫 生殖 皮肤 疼痛 影像学 神经系统 肾脏 消化系统 血液肿瘤 移植 妇科 疫苗

www.fountain-med.com
54
方恩质量—接受并通过现场核查
# Therapeutic Area Phase Sponsor Date Authority Inspection for Conclusion
1 sarcoma III Global sponsor 2010 FDA Site GCP certification re-new Pass
2 CV III Global sponsor 2013 EMEA Site GCP certification re-new Pass
3 Dermatology III China local sponsor 2014 CFDA Site GCP certification re-new Pass
4 Dermatology III China local sponsor 2015 CFDA Site GCP certification re-new Pass
5 Dermatology III China local sponsor 2015.6.24 CFDA Site GCP certification re-new Pass
6 Dermatology III China local sponsor 2015 CFDA Site GCP certification re-new Pass
7 Dermatology III China local sponsor 2015 CFDA Site GCP certification re-new Pass
8 Dermatology III China local sponsor 2016.8.9 Guangdong PFDA NDA Pass
9 Dermatology III China local sponsor 2016 CFDA Site GCP certification re-new Pass
10 Diabetes I China local sponsor 2015.4.23 Jiangsu PFDA Supplemental application Pass

11 Focal Liver Lesion III Global sponsor 2015.12.25 TFDA NDA Pass
12 Gastroenterology III Global sponsor 2016.1.25 Guangdong PFDA Site GCP certification re-new Pass
Ultrasound Contrast
13 III Global Sponsor 2017.6.16 CFDA NDA Pass
Agent
14 Psoriasis III China local sponsor 2017.7.21 CFDA NDA Pass
15 Psychiatry I Global sponsor 2017.7.21 CFDA NDA Pass
16 Psychiatry I Global sponsor 2017.6 CFDA NDA Pass
17 Psychiatry I Global sponsor 2017.6 CFDA NDA Pass
18 Ceus I Global sponsor 2017.6 CFDA NDA Pass
19 Vaccinology III China local sponsor 2018.9 NMPA NDA Pass
20 Oncology III China local sponsor 2019.3 NMPA NDA Ongoing
方恩品质 – 客户稽查均已成功

 目前已有超过 70+ 家医药、器械公司对方恩进行 CRO 系统稽查，均已成功通过

 其中包括罗氏、诺华、雅培、拜耳、百时美施贵宝、辉凌、强生、默克、

先灵葆雅、施维雅、葛兰素史克、通用、波士顿科学，赛诺菲，阿斯利康，

美敦力等客户

56
国内项目汇总– 2019 治疗领域 数量 比例
心血管疾病 3 2.1%
项目经验分期 皮肤疾病 3 2.1%
2.10% 医疗设备和诊断仪器 / 试剂 12 8.4%
内分泌疾病 8 5.6%
8.40%
消化系统疾病 1 0.7%
血液系统疾病 1 0.7%
免疫系统疾病 5 3.5%
16.10% 37.80%
感染性疾病 7 4.9%

代谢和营养相关疾病 6 4.2%
骨骼 - 肌肉疾病 1 0.7%

神经系统 / 中枢神经系统疾病 9 6.3%

肿瘤 70 49.0%
21.70% 眼科疾病 6 4.2%
呼吸系统疾病 5 3.5%
14.00%
泌尿系统疾病 2 1.4%
疫苗 1 0.7%
I期 II 期 III 期 IV 期 医疗设备 其他
女性生殖健康 3 2.1%
数统经验 - FDA 递交经验
Submitted to Approved by First Cycle Priority
治疗领域 - 疾病
FDA 递交 37 个产品的 过敏性疾病
FDA
2
FDA
2
Approval
1
Review

抗感染治疗 1

178 个项目，全部接收 心血管疾病 / 高脂血症

中枢神经系统疾病
2
9
1
5
1
3
1
1
皮肤科疾病 2 1 1
24 个已通过 糖尿病 1 1 1
消化系统疾病 1 1
7 个在审 代谢异常疾病 2 1 1
肿瘤 7 6 6 4
6 个需要补充试验 眼科疾病 4 3 3 1
罕见病 1
呼吸系统疾病 3 2 3
泌尿系统疾病 1
女性生殖 1 1
总计 37 24 20 7
NMPA 递交项目经验 – 3 年内

治疗领域 产品数目 试验数目 备注

免疫性疾病 1 2 (I, III) Biosimilar
营养和代谢疾病 7 9 (I*4, III*5) New drugs
心理疾病 1 2 (I*2) License In
疫苗 1 1 (III*1) New drug
肿瘤 3 3(I*1 ， III*2) New drug
感染性疾病 3 5 (II*2, III*2, BE*1) New drug
诊断试剂 3 4 (Device*4) New drug
总计 19 26
CDE 现场核查经验 (2017-2019.6)

治疗领域 分期 项目数 适应症

I 1 超声造影剂
诊断试剂
III 1 超声造影剂
I 1 强直性脊柱炎
免疫系统疾病
III 1 强直性脊柱炎
III 1 乳腺癌
肿瘤 100% 通过核查
III 1 非小细胞肺癌
精神 / 心理性疾病 I 2 精神分裂症
疫苗 III 1 子宫颈癌疫苗
营养和代谢疾病 III 2 高脂血症
II 1 丙型肝炎
感染性疾病 III 1 丙型肝炎
BE 1 乙型肝炎
总计 14
数统团队中美双报项目经验

治疗领域 I期 II 期 III 期 共计

缺血性脑卒中（健康人药代） 2 2

胸腺癌 1 1

非小细胞肺癌 1 1

淋巴瘤 1 1

乳腺癌化疗后粒细胞刺激因子 3 1 1 5

眼科 1 1

疫苗 1 1

总计 7 2 3 12
 THANK YOU

张丹
Dan.zhang@fountain-
med.com
136 1114 2168

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