外資系企業における承認及び開発品目の傾向～PhRMA/EFPIA合同調査結果より～○秋本美紀1、池田晶子1、青木勇1、伊藤優子1、宇都宮聡子1、榎本朱美1、砂村一美1、日高正泰1、森久保典子1、前田玲1、小野嘉彦1、茶木啓孝2、岩井葉子2、佐々木一尋2、喜多村英明2、大澤正樹 2、伊藤泰章2、横田尚久2
1
米国研究製薬工業協会（PhRMA） 2欧州製薬団体連合会（EFPIA）

PhRMA/EFPIAで実施した2017年度の合同調査結果は以下の通りであった。
審査期間と承認品目
・ 2017年度（2017年4月～2018年3月）にPhRMA及びEFPIA加盟会社で承認された新医薬品は54品目で、そのうち通常審査品目は31品目であり、審査期間は80%tileで11.2ヵ月であった。
公知申請を含む優先審査品目は23品目で、70% tileで9ヵ月であった。
・ 審査期間のラグは解消してきているが、同時申請にはまだ改善の余地があり、早期開発戦略の検討、諸制度の活用及び国際調和による日本特有の要件の緩和があげられる。
・ 日米欧での迅速制度の利用状況については、FDAで一番多く複数の制度が利用されており、制度の利用状況には品目によって当局別で差があった。
開発品目
・ 2017年度に開発中のプロジェクト数は527であり、668試験が実施されていた。そのうち国際共同治験は493試験であり、74%を占めていた。また開発中のプロジェクト数のうち約半数は新有効成分であった。
疾患領域として抗悪性腫瘍薬が多く、全体の49%を占めていた。また欧米と同時申請を目指しているものは全体の61%を占めており、増加傾向にあった。
・ 先駆け審査指定制度は、外資系企業の指定希望の割合が依然として低く、比較して米国、欧州の早期承認制度（Breakthrough、PRIME）指定希望の割合が高かった。
・ 小児開発については、全プロジェクトのうち18%程度で開発が進められており（予定を含む）、半数が成人適応承認後の後追い開発であった。
国際共同治験に参画する前の対面助言は約半数の47%で行われた。対面助言によりプロトコール変更の指示は48%に認められた。そのうち日本人症例数の変更指示は35%であり、その54%で指示通りに症例数を変更した。
●PMS調査PMS調査は承認品目の81％で実施され、その半数は全例調査であった。2018年4月に施行された改正GPSP省令の影響により、データベースを用いた調査も7％実施されている。改正GPSPの浸透、更にはICT基盤法施行に伴い、今後データベース調査の更なる増加が期待される。
●Review PeriodIntroduction
PhRMA/EFPIA Performance Metrics Survey 2018

The Number of Drug Approvals in Japan

Executive Summary of the Survey

134

Products130• Scope:• Review Time

117

112

Review Time

– Drug approvals in FY2017– Background, Review time
– Regulatory Pathways in JP, US and EU

*138
112
104

– Drugs approved in FY2017 (April 2017 to March 2018)91

Global and Local Studies– Clinical studies initiated/continued/completed during FY2017• Global Study and Local Study61• Companies involved:

555657– Number of Global and Local studies– Therapeutic area of Global and Local studies– Interaction with the Agency

544137

PhRMA (11 companies)– Abbvie, Alexion, Amgen Astellas BioPharma, Biogen Japan, Bristol-Myers Squibb,Celgene, Eli Lilly, Janssen, MSD, Mundipharma, and Pfizer• PMS

EFPIA (17 companies)– Baseline data of PMS in approved projects– Actelion, AstraZeneca, Bayer, CHUGAI, CSL Behring, Ferring, GlaxoSmithKline,Janssen, LEO, Lundbeck, Merck Serono, Boehringer Ingelheim, Novartis, Novo
Nordisk, Sanofi, Shire, and UCB

Key findings:
In FY2017, approvals of EFPIA+PhRMA (54)account for over 50 % of total number (104)*: Paper JNDA : Public knowledge-based
application with preliminary assessment

Priority Review Including Paper JNDAs

Standard Review

Rate of Orphan was 22% (12/55)
in EFPIA+PhRMA in FY2016(increased by 10%)MonthsMonths

Review Category of Approvals in FY2017

Rate of Orphan was 23%(26/112) in ALL in FY2016(increased by 2%)

116FY2010

FY2011FY2012FY2013

FY2014FY2015FY2016FY2017FY2010FY2011FY2012FY2013

FY2014FY2015FY2016FY2017

MedianMedianMedianMedian60%tile70%tile70%tile80%tileMedianMedianMedianMedian60%tile60%tile70%tile70%tile

ALL

14.7

11.5

10.3

11.3

11.9

11.3

11.6

11.8

ALL

9.2

6.5

6.1

7.2

8.8

8.7

8.8

8.9

PhRMA

14.5

10.4

10.7

10.8

11.2

11.7

11.3

11.2

PhRMA

12.0

6.2

4.9

7.2

8.1

8.1

8.6

8.7

EFPIA

11.1

9.9

11.4

11.3

11.0

11.2

11.5

11.2

EFPIA

8.8

6.5

6.17.5

11.0

9.0

8.1

9.0

Key findings : The rate of Orphan in PhRMA + EFPIA vs ALL accounts for 63% (17/27)
in FY2017 and the rate of Orphan is higher than 26% in all and 32% in PhRMA+EFPIA

Key findings : 80% of cases for Standard Review in FY2017 were completed less than
12 months, the PMDA’s targeted review time.

Category of New Drug Approvals
including NME and LCM

Impact on Development Plan andSubmission Timeline after PMDA Consultation

PhRMA+EFPIA (N=54)

Key findings : 70% of cases for Priority Review in FY2017 were completed less than9 months, the PMDA’s targeted review time, including paper JNDAs.

Simultaneous JNDA Filing
PhRMA+EFPIA (N=54)
Actual result of simultaneousFiling （N=26)

ReasonType of pivotal study

Review Team

Pre-JNDA

Requested comparator

Office 4
Infection

EoP2

Less than 3M

Requested dose finding study
in Japanese

Office 4
Antimicrobials

BeforePre-P2

1Y or more

Denied clinical data package

Office 5
Oncology

Pre-JNDA

more than 3M
and less than 1Y

Office 5
Oncology

Pre-JNDA

Utilization of Expedited Program
PMDA (N=51)
Conditio-nal
EarlyApproval

Sakigake••••••••

Prioritize product development
Secure resources including Global
Evaluate unmet medical needs in Japan
Construct processes that enables
determination of development at an earlystage in Japan
Make Japan development strategies at anearly stage and align with global
Get a consensus for CTD preparation scheme
at an early stage
Consider the timing of licensing-in of productfrom other company••••

Priority
Review

Orphan

PR
PR
PR
PR
PR
PR
PR
PR
PR
PR
PR
PR
PR
PR
PR
PR
PR
PR
PR
PR
PR
P-JNDA

Promote utilization of the current regulatory
system and Strengthen PMDA organizationAccept CTD in English and relax the Japan
specific requirement for CTD preparation
Review and revise Japan specific GL, e.g., longterm clinical study for chronic disease
Promote globalization of CMC documents
and Japan pharmacopoeia
Be flexible to accept global clinical data andjoining MRCTOrphan
OrphanOrphanOrphanOrphanOrphanOrphanOrphanOrphanOrphanOrphanOrphanOrphanOrphanOrphanOrphanOrphanAccelerated
Approval

1Y or more

BTD
BTD
BTD
BTD
BTD
BTD
BTD

AA

Fast Track
FT
FT
FTAA
AAAA

Priority
Review

Orphan

PR
PR
PR
PR
PR
PR

PRIMEOrphan
OrphanOrphanOrphanOrphan

PRIME
PRIME

OrphanOrphanOrphanFT

Condi-tional
Exceptional
AcceleMarketing
Circumstanc
rated
Authories
Assessment
zation
CMA
AA
AA
AA

---

PR
PR
PR
PR

FT

BTD

OrphanOrphanOrphanOrphanOrphanOrphanOrphan

PR
PR
PR
PR

BTD
BTD
BTD
BTD
BTD

OrphanAA

OrphanOrphanOrphanOrphanOrphanAA

OrphanAA

OrphanOrphanOrphanOrphanOrphanOrphanOrphanOrphan

AAAA
AA

AA
AA

PR

••
•

Expedited program is widely used in the 追加調査用スライド
US. But the variety of program is
同時申請計画していない→何がFurther Analysis
resultAuthorities.
comparable between
3 Health
原因か→詳細な理由を述べる（砂村さん、秋本）
FDA was the agency with the shortest approval time in 2017 (243days),
likely due to the wide use of these pathways*.
16/51 projects(31%) were reviewed as standard in JP/US/EU

Facilitated Regulatory Pathways

PMDA (n=51)

FDA (n=51)

EMA (n=49)

Sakigake, Breakthrough Therapy
PRIME

013 (25%)

3 (6%)

Conditional Early Approval
Accelerated Approval
Conditional Marketed Authorization

07 (14%)2 (4%)

Fast track

08 (16%)0Priority Review
Accelerated Assessment

22 (43%)24 (47%)9 (18%)

Orphan17 (33%)

17 (33%)14 (29%)Projects utilizing at least 1 Pathway(s)22 (43%)34 (67%)17 (34%)OrphanPRPRPRPRIME

AA
PR
PR
PR
PR
PR
PR

FT

Reason of “No”:•Internal condition at Company(6) Japan specific document preparation (2) Others (4)•Not enough Scientific evidence to support
simultaneous JNDA(1)•Delay by PMDA’s requests（2）Reason of “No”:•Japan local development (3)•Already approved outside Japan (11)•Difficult to join global pivotal study (3)•Additional study requests by PMDA (2) Dose setting in Japanese (1) Other (1)•High priority outside Japan (2)•Japan specific document preparation (2)•Others and unknown (5)CMAFTNoKey findings on Expedited Programs

EMA (N=49)

OrphanKey Findings:•Yes (within 3 months)

PhRMA+EFPIA

FDA (N=51)
BreakthroughTherapy

FT•

9Key findings :Development plan had to be changed and Submission schedule had
to be delayed due to requests by PMDA at PMDA consultation

Key findings : Majority of new drugs were New active ingredient (46%) and new indication (39%)
Type of pivotal data consisted of global studies (59%), and local studies (29%)
33% of the drug were reviewed by office 5, Oncology. Next portion (31%) was reviewed by the office 4.

To HAs :1Y or more

17Office 2
Cardiovascular

PhRMA+EFPIA (N=54)

By Applicant(s) :Length of thedelay

Requested local study basedon the GL

Denied Interim Analysis

Suggestions for Improvement on the Submission Lag

Timing ofPMDA
consultation-----

NOT simultaneous submission from the beginning:
The delay to start development in Japan, not participation in MRCT, required additional CT and thenecessity of preparing documents for JNDA requested by PMDA
Not achieved simultaneous submission:
The necessity of preparing documents for JNDA, the additional request from PMDA and one casedue to clinical trial results

51 products submitted to both PMDA and FDA, of which 49 products submitted to EMA.

* Centre for Innovation in Regulatory Science(CIRS), May 2018, R&D Briefing
One line shows one product submitted to PMDA/FDA/EMA. 51 products submitted to both PMDA and FDA, of which 49 products submitted to EMA.

Clinical Studies and Development Plan
Submission Lag (months) including NME and LCM

Total Projects in FY2017

Development Status in FY2017
527 projects

PhRMA+EFPIA 527 projects
Key findings:
 Total project number is 247
for PhRMA, and 527 for
PhRMA+EFPIA are on-going.
The ratio of NCE is 51%.

Key findings:
 The target products of simultaneous submission are planed 61%.

Blue: Did NOT aim simultaneous filing
Red: Aimed simultaneous filing

PhRMA+EFPIA

Note: The following data include the studies already completed or terminated regardless ofreasons in addition to ongoing studies

Therapeutics Area

Development for pediatric patients

SAKIGAKE/Breakthrough(BT)/PRIMEPhRMA+EFPIA data (Total: 527 projects)

Development plan for pediatric patients

PhRMA+EFPIA 527 projects

Unknown, N=2, 0%

Development schedue

Planning ordeveloping,
N=94, 18%

Plan for SAKIGAKE

Prior to adults,
N=9, 10%
Simultaneously,
N=33, 35%

YES,
N=38,7%

Following adults,
N=52, 55%

NO,
N=489,93%

Key findings:
 The number of projects that plan for SAKIGAKE designation
are planed 38
 The number of projects that plan for BT and PRIME are 71(BT), 57 (PRIME), is more than the one of SAKIGAKE

Metabolic
Oncology
Blood product
CNSCVDigestive
Anti VirusAllergy
Respiratory
Anti bacteria

Key findings:
 18% of projects have a plan for the development
for pediatric patients. Over 50% of projects areplanning to develop for pediatric patients
following the development for adults.

Key findings:
 The ratio of Oncology development is 49%, and major
target area.

Total Number of Clinical Studies (Global/ Domestic)
Conducted by PhRMA + EFPIA

Therapeutics AreaNo,
N=431,82%

Clinical Studies in FY2017(Phase, Global/Domestic, Oncology/Non-Oncology)

15 Hormone
11 Regenerative medicine
11 Immunosuppressant
10 PN
8 Anesthesia7 Sensoria
4 Urinary
4 Vaccine
4 Others
3PMDA Consultation/ Pre-meeting
before starting MRCTPhRMA+EFPIA data (Total: 646 studies)

PhRMA+EFPIA (493 global studies)

In this analysis, 22 studies are excluded from total 668 studies because ofa withdrawal (10 studies) or under review (12 studies).

Oncology

Ph162
Ph1/2 18 24
Ph2a 512
Ph2b 1372
Ph2/3 5 17Ph3
63052

Ph1, Ph1/2

31110038

Domestic

150

200

250

300

350

PMDA consultation,
N-231, 47%

Nomeeting,
N=160,64%38
Oncology

15850Others

230
100150200250

300

350

PMDA
consultation,
N=66, 26%

Pre-meeting
only, N=26,10%Pre-meeting
only, N-48,10%400

640No meeting,N-214, 43%

303

Ph2/3, Ph3

Key findings:
 Total study number in FY2017 was 668 for PhRMA+EFPIA.
 The ratio of Global studies was about 74% in FY2017, and it has increased for the past fewyears.

45 Alzheimer
1 Respiratory
1 Blood product

Global118

Ph2a, Ph2b

Late phase (Ph2/3 and Ph3)

Therapeutics area of Ph1 global studies
Oncology
Metabolic
Urinary

5080%, N=222

Question on Protocol design
Request for Protocol change

400Key findings:
 54% (62/114) of Ph1 studies were conducted in domestic, but in late phase, global
development was major strategy.
 The rate of oncology studies is higher in early phases.

48%, N=106

Request for change of number ofJapanese

35%, N=37

Actual change of number ofJapanese

54%, N=200

50

100

150

200

250

300

No meeting,
N=121, 38%

PMDA
consultation, N=182,57%

Pre-meeting only,
N=17, 5%

Key findings:
 PMDA consultation or Pre-meeting wereheld before starting MRCT at the rate of57%.
 Protocol change was requested byPMDA at 48% of consultations onprotocol design.
Change of Japan subject number wasrequested at 35% of consultations
requested for protocol change, and 54%of them changed the number actually.

PMS Survey from approved projects in 2017
All-case surveys are 50% because many orphan drugs got approval in 2017.

Detail of PMS Survey

Conduct All-case surveys(ACSs)

Number of surveys per products(Indication)

Conduct PMS surveys
NoYes

No

10,19%

22,50%

44,81%

Category of Indication in All-case surveys (ACSs)

Rheum
atism, 1

Not-Pedi
4,18%

22,50%
N=44N=54PediatricYes
Key findings:• ACSs are 50%• Most of orphan
drugs andRheumatism’s
drug areconducted ACSs

3 surveys
2 surveys
1 survey

Others, 5Orphan, 1038

NA
3000～
2000～3000
1000～2000
500～1000
300～500～300

EDC
16, 36%

NA>5Y
3Y～5Y
2Y～3Y
1Y～2Y
<1Y

2Y～3Y

HybridNA>3Y
2Y～3Y
1Y(52W)～2Y
24～52W<24W

20, 46%

3Y～5Y>5Y

NA: Not set based on all

22NoYes

14, 7%

7

PhRMA:3, EFPIA:1

824

24～52W

1Y(52W)～2Y

2Y～3Y>3YNA

10N=5436Numbers of Database survey

Database Survery

0<24W

Expected Enrollment period
1Y～2YDatabase survey in PMS

Observation period/1 case8, 18%<1YRheumatism, 3

5Numbers of patients in a survey

Type of Survey form

Orphan,318,82%

N=441Paper22
111
11
17>4Surveys

13 Surveys

22 Surveys

11 Survey

0JMDC

0

What database will be used ?

MDV

2MID-…

250, 93%

Cost of Database survey

8225NA10678194

Key findings: The reason of the result for coverage of ACSs (50%), # of patients and type ofsurvey form is orphan drug. 75% of ACSs are conducted using for Hybrid. It assumes that100~300 mil yen are needed to conduct PMS those are “enrollment period is 1~2 years” and“observation period is 24~52W”.

>300 Mil Yen

0100～300Mil Yen

2<100 Mil Yen

2

Key findings: The result is limited because only 4 companies conduct database survey.
The result suggest that database survey will be conducted more than one perproduct(indication) and cost is needed 100~300 mil yen.

Usage of PMS Data (Not only database survey)
All companies (21 companies) answered
Use PMS results /data for “Re-examination”, “ Report to investigators”,“Publications”