Recent Regulatory Changes in Chinaand Impacts to the Clinical Trials
from CRO Standpoint

China New Regulatory

New Drug Approval System Reform
The State Council
08Oct2017

Optimize Clinical Trial Process
In the Past
IND

Encourage
Innovations andGenetic Drugs

Phase 1QualitySite•

Generic drug consistency
evaluation•MAH (Marketing Authorization
Holder) System•

NDA in parallel with othercountries without CPP

New Policy

8-12 months

60 Working Day notice period.

Only after foreign region has
phase 1 data.

Parallel early phase in China

Clean the IND/NDA backlog byquality inspections.

Legal actions against fake data

GCP site accreditation
Each site has its EC.

Online Registration (Future)
Regional EC / Central EC (Future)IEC

Accelerate new Drug Approval
In the Past
Unmeturgent needRare
DiseaseNew Policy

NAConditional approval on earlyclinical evidence

NAIssue China rare disease list,
priority review and approval

Approval onForeign
China study for NDA registration
Datapurpose.

© 2018 All rights reserved | Confidential | For Syneos Health™ use only

Guideline on MRCT data
acceptance, NDA approval basedon MRCT result.

MAH: Marketing Authorization Holder
CPP: Certificate of a pharmaceutical product.

4Clear IND/NDA Backlog and Inspection on Quality
25000

CFDA reducing
backlog

22000

20000
18500
15000

14235

10000

Backlog

12068

11286

Finished

9746

From 22,000 cases(mid-Year2015) to4,000 (Year 2017)

9680

9601
8200

5000

4783

5510

4660

5261
4000

0
2011

2012

2013

2014

2015
22Jul2015

2016

2017

Inspection on Quality• 22Jul2015: CFDA announced to have on siteinspections• Two years after till Jul2017• 65% application withdrawn by sponsor• Finished inspections on 313 NDA applications• 185 inspection team (1635 person-time)• 763 site-time

146,7%

Sponsor Withdraw

258, 13%
Inspected
313, 15%1316, 65%

Waiver to Clinical TrialWill Inspect© 2018 All rights reserved | Confidential | For Syneos Health™ use only5Legal Actions Against Clinical Trial and Marketed• Legal actions in case of fraudulent activities (Year 2015-2017 Summary)•Finished inspections on 313 NDA applications•38 NDA may have the fake data, 30 NDA were rejected•

Legal actions against to 11 sites and CROs

• China sacked top officials over vaccine scandal (Jul-Aug 2018)– 252,600 doses DPT (diphtheria, whooping cough and tetanus), plus rabies vaccine

couldn’t meet the standard of immunity results– 18 suspects were detained– 7 senior government officials were punished• Bi Jingquan, former CFDA head resigned• Wu Zhen, one NMPA former deputy head, was investigated on anti-corruption• Two deputy governors of Jilin Province were dismissed or resigned© 2018 All rights reserved | Confidential | For Syneos Health™ use only6

More and quicker Innovation IND Approvals•••••Encourage China innovative drug to be developed in parallel with other global countries
Number of chemical innovation IND approvals increased to 170 in 2017
The average IND first-round review timeline was 120 working days
The average priority IND first-round review timeline was 39 working days
CDE consultation meetings for pre-IND, IND, phase 1, phase 2 and pre-NDA
Chemical Innovation China IND Approval

180

170

160
131

120

840

700
600

100

91

87

500

60

400

40300

202000100
2014

•900
800

14080

CDE Consultation Meeting2015

2016

2017

336321

184
118
540Innovation: New medicine that was never approved globally.

© 2018 All rights reserved | Confidential | For Syneos Health™ use only

Meeting Hold

Meeting Applied

7Accelerate New Drug Availability
NDA Acceleration
Urgent Unmet Need& Rare Diseases

Global Data for China NDA

Gardasil 9Oncology Medicine NDA
Approval closely after US-FDA

8 days, global data only

GlobalData forChina
NDA

20Apr2018: NDA Applied
28Apr2018:
Conditional approval for female
16-26 age

15Jun2018: Nivolumab
25Jul2018: Pembrolizumab

Based On:Rare Diseases••

Global clinical dataSome East Asia data•

Monitoring China subjects
post-marketing.

Early Accessible
prior to NDA ApprovalSpecial approval at Hainan“Super-Hospital”• New FDA-approved drug could
be accessible even before
China NMPA approval• New medical device can beapproved by Hainan province.
(Normally approved by NMPA)

11May2018:
China published its Rare Disease List

Accelerate NDA Approval:

In the Past

Cervarix
10 years to enter China
Jul2016: China approval•••

Priority Review for “Breakthrough”
Conditional approval
Pre-IND / ongoing CDE meeting© 2018 All rights reserved | Confidential | For Syneos Health™ use only

https://mp.weixin.qq.com/s/C
zO3_1yPgxr52MpLMRlZUA8

New Policy Impact onChina Market

China Market Change Overview
Affordable Medical Coverage

Genetic DrugInnovation• Optimize Clinical Trial Process• First-in-man trial in China• Global data for registration in China• Generic drug consistency evaluation• Price sensitive with large volume

CRO View Point
Increasing Need
• High quality at global standard• First-in-class: will be in the future• Me-too / Me-better are very competitive now

Increasing Need
• BE (Bioequivalence) study• Matthew effect (The strong pharm got stronger)

Decreasing Need
• Few China-only registration trial

Decreasing Need
• Hard time to low level and poor quality pharms© 2018 All rights reserved | Confidential | For Syneos Health™ use only10

New Policy Impacts on China Market• Encourage the first-in-class drug development in China, parallel to US/EU– Shorten start up timeline and process in China (best scenario 7-8 months)– Encourage Phase I in China in parallel with globe– Pre-IND meeting with CDE to minimize the clinical development risks• Me-too / Me-better will be much competitive• Better quality with global ICH standard• Generic drug bioequivalence is on the fast track• To provide the affordable medical insurance coverage© 2018 All rights reserved | Confidential | For Syneos Health™ use only

11

China Innovative INDs among 170 Indications

The graph only includes thoseinnovation medicines which are neverapproved globally

Others10%
Hematology
4%

••
•

Anti-infective
5%
Rheumatology
immunology
5%

Oncology (72 cases, 42%)
Digestive (26 cases, 15%)
Endocrinology (12 cases, 7%)

Oncology42%•
Circulatory system
6%•PD-1 and PD-L1 are the hottest
developing area
Me-too or Me-better from Chinabase global ambition companies

Neuroscience
6%

Endocrinology
7%
Digestive system
15%© 2018 All rights reserved | Confidential | For Syneos Health™ use only12

PD-1 / PD-L1 Landscape in China
PD-1 / PD-L1 Key Players:

Marketing Approval in China:• Global pharms lead the market.

15Jun2018: Nivolumab (Opdivo, BMS) for lung cancer• Four leading China-based pharms closely follow-up

25Jul2018: Pembrolizumab (Keytruda, MSD) for local advancedor metastatic melanoma.

• 20+ companies, highly competitive.

CompanyBMS
MSD

CompoundPD-1 / PD-L1
Stage
Nivolumab(Opdivo)
PD-1
MarketingPembrolizumab(Keytruda) PD-1
Marketing

Shanghai Junshi (君实)Heng Rui (恒瑞)Innovent (信达)JS001
SHR-1210
IBI308BeiGene (百济)RocheMerck/Pfizer
AZ
AlphamabGloriaCStoneHengRui
Bio-Thera
Akesobio
Kelun
LivzonCHIATAI TianQing
Lee's Pharm
HenliusCStoneHenlius

BGB-A317
Atezolizumab (Tecentriq)
Avelumab(Bavencio)
Durvalumab(Imfinzi)
KN035
GLS-010
CS1001
SHR-1316
BAT1306AK103
KL-A167
LZM009
TQB2450
ZKAB001
HLX10CS1003
HLX20

PD-1
PD-1
PD-1
PD-1
PD-L1PD-L1PD-L1PD-1PD-1PD-L1PD-L1PD-1PD-1PD-1PD-1
PD-L1PD-L1PD-1
PD-1
PD-L1NDA
NDA
NDA

PD-1/PD-L1 Cancer Trials in China:
HCC
NSCLC
Esophagus Cancer
Melanoma
Hodgkin Lymphoma
T-Cell / NK-Cell Cancer
Urothelium Cancer
Gastric Cancer
SCLC
Breast Cancer
Renal Cancer
Nasopharynx Cancer© 2018 All rights reserved | Confidential | For Syneos Health™ use onlyAYYYYYYBYYYYYYCDYYYYYEYYYYYYYYYYYYY

A, B, C, D, E are different companies.

13

Generic Drug Consistency Evaluation

289 Categories
listed by NMPA
Need to finish BE
studies by end-2018

Around 60 Sites
can take BE trials

Clinical Cost
RMB 4-6 million

Site resources arelimited(JPY 65-98 million)
per trial

Only 13 past by Sep

GenericMedication
Overview

Eliminate backward
production capacity

Procurement quantitywith low price© 2018 All rights reserved | Confidential | For Syneos Health™ use onlyMatthew effect14Overview

China Market Future View

Trial Landscape
Early Phase•

Build phase 1 centers of excellenceFirst in Class•Chinese KOLs have more access to membership of steeringcommittees in global trials

China onlyregistration•

Global development strategy to include China from the very beginning.

China Site•••

Better Trial
infrastructures

Operational ReadinessPatients•

More innovative trial•

Skilled professional staff•

More patient education•

Resourced requirement
for clinical staff•

More Data sharing•

Global standards

Upskill of site staff
New clinical trial sites© 2018 All rights reserved | Confidential | For Syneos Health™ use only16