Submission lag between US/EU Free comments...2019/09/02 ·...

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～ ○本庄香織（ノバルティスファーマ）1、大澤正樹（シャイアー・ジャパン）1、岩井葉子（アストラゼネカ）1 、佐々木一尋（ヤンセンファーマ）1、花久恭子（ルンドベック・ジャパン）1 、篠田好果（ノバルティスファーマ） 1、

茶木啓孝（バイエル薬品）1 、伊藤優子（アステラス・アムジェン・バイオファーマ）2、秋本美紀（ブリストル・マイヤーズスクイブ）2 、池田晶子（ヤンセンファーマ） 2 、青木勇（ブリストル・マイヤーズスクイブ） 2 、榎本

朱美（日本イーライリリー）2 、武澤恵美子（セルジーン）2 、砂村一美（ファイザーR＆D）2 、春日井正文（アステラス・アムジェン・バイオファーマ） 2 、武部恭子（ヤンセンファーマ） 2 、穂積香織（アッヴィ）2、前田玲

（日本イーライリリー） 2

1欧州製薬団体連合会（EFPIA） 2米国研究製薬工業協会（PhRMA）

COI開示：演題発表内容に関連し、発表者らに開示すべき利益相反はありません。

PhRMA/EFPIAで実施した2018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

● 2018年度（2018年4月～2019年3月）にPhRMA及びEFPIA加盟会社で承認された新医薬品は59品目で、そのうち通常審査品目は30品目であり、審査期間は80%tileで11.8ヵ月であった。公知申請を含む優先審査品目

は29品目で、80% tileで8.7ヵ月であった。

● 日米欧の審査期間はほぼ同じであり、審査期間のラグは解消されていることが示された。よって、日本における承認時期の欧米との差は、申請時期の差によるものとみられた。

● 日米欧での先駆け審査指定制度、Breakthrough指定制度、PRIME指定制度等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当局別で差があった。

開発品目

● 2018年度に開発中のプロジェクト数は674であり、792試験が実施されていた。全試験のうち、第Ⅱ相、第Ⅲ相試験では国際共同試験が80%を占めており、多くの品目で海外と同時に開発が進められ、60％以上の品

目で同時申請を予定していることが示された。疾患領域として抗悪性腫瘍薬が多く、全体の55%を占めていた。

● 外資系企業における先駆け指定を希望する品目は5%と低かった一方で、3か月以内の申請予定は6割以上であった。

● 小児開発については、全プロジェクトのうち18%で開発が進められており、うち約40%が同時開発であった。

PMS

● PMSは承認品目の75％（44品目でPMS49件）で実施され、うち全例調査は31％であった。データベースを用いた調査はPMS全体の18％を占めており、昨年度と比較し増加していた。これは改正GPSPの浸透に伴うもの

であると推察される。

Review Time for Standard Review

3

6

9

12

15

FY2010 FY2011 FY2012 FY2013 FY2014 FY2015 FY2016 FY2017 FY2018

ALL PhRMA+FEPIA


Median Median Median Median 60%tile 70%tile 70%tile 80%tile 80%tile

ALL (PMDA) 14.7 11.5 10.3 11.3 11.9 11.3 11.6 11.8 11.9

PhRMA+EFPIA 11.1 11.4 11.3 11.7

Mo

nth

s

Key findings: Both review time for “Standard Review” in FY2018 were less than 12 months in 80%tile.

2

Review periodReview Time for Priority ReviewIncluding Paper JNDAs

0

3

6

9

12


ALL PhRMA+EFPIA

Mo

nth

s

Key findings: Both review time for “Priority Review” in FY2018 were less than 9 months in 80%tile.


Median Median Median Median 60%tile 60%tile 70%tile 70%tile 80%tile

ALL (PMDA) 9.2 6.5 6.1 7.2 8.8 8.7 8.8 8.9 8.6

PhRMA+EFPIA 9.2 8.3 8.8 8.7

3

The Number of New Drug Approvals in Japan

112

130134

138

117 116112

104

118

37

57

81

41

6156 55 54

59


ALL PhRMA+EFPIA

Key findings: In FY2018, approvals of EFPIA+PhRMA (59) account for 50 % of ALL (118).

4

Proportion of Review Category for FY2018 Approvals

N=7059% N=30

51%

N=3731%

N=2644%

N=119%

N=3, 5%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

ALL (PMDA)N=118

PhRMA+EFPIAN=59

Paper-JNDA

Priority Review

Standard Review

Key findings: Proportion of Priority Review (including Paper-JNDA) in PhRMA+EFPIA accounts for 49%, which is larger than the one in ALL 41%.

5

Additional Analysis for FY2018 Approvals

Bio, N=28,47%

Non-Bio, N=31, 53%

Bio or Non-Bio

New active ingredient, N=20, 34%

New combo, N=2, 3%

New route, N=1, 2%

New indication, N=27, 46%

New dosage, N=5, 9%

Biosimilar, N=2, 3%

Regenerative medicine, N=2,

3%

Category of New Drug Application

PhRMA+EFPIA (N=59)

1

1

3

1

4

1

5

12

2

21

2

2

2

2

Office 1 (GI)

Office 1 (Metabolic)

Office 2 (CV)

Office 2 (Reproductive)

Office 3 (CNS)

Office 3 (Sensory)

Office 4 (Antimicrobial)

Office 4 (Respiratory)

Office 4 (HIV)

Office 5 (Oncology)

Reproductive medicine

Bio-CMC

Vaccines

Blood Products

Review Category

(36%)

“New indication” (46%) and “new active ingredient” (34%) were the majority of the category of the NDA.Oncology (36%) was the largest review category. 6

Additional Analysis for FY2018 Approvals

Yes, N=12, 20%

No, N=47, 80%

Approved indication including “pediatrics”

Global Study, N=34, 57%

Local Study, N=13, 22%

Extrapolate Overseas Data

N=7, 12%

Paper-JNDA, N=4,

7%

Skip Ph3 (Ph2=Global), N=1, 2%

Type of Pivotal Study

PhRMA+EFPIA (N=59)

Key findings: Type of pivotal study consists of “Global studies” (57%), “Local studies” (22%) and “Extrapolation of overseas data” (12%). Proportion of approved indication with pediatrics accounts for 20%.

7

Simultaneous JNDA filing

YesN=2648%

YesN=2136%

NoN=2852%

NoN=3864%

0%

20%

40%

60%

80%

100%

FY2017 FY2018

Aiming simultaneous JNDA filing(within 3 months) at the planning phase

Achieved, N=15, 71%

Not achieved, N=6, 29%

Result of simultaneous JNDA filing within 3 months (N=21)

Reason of “Not achieved”• Due to the internal circumstances

at Company (4 cases)• Needed to respond to PMDA’s

request (2 cases)

PhRMA+EFPIA

(N=59)(N=54)

Key findings: 36% of approvals planned simultaneous JNDA filing and 71% of those drugs achieved simultaneous JNDA filing

8

Total Projects in FY2018

Key findings : In FY2018 the total number of ongoing projects are 674 . The ratio of new MOA increased from 54% (FY2017) to 72% in FY2018 . The products with plan of simultaneous submission are 63%, slightly increased from 61% in FY2017.

NCE, 310, 46%

New indication, 296, 44%

New dosage, 27, 4%

FDC, 12, 2%

New administration, 9, 1%

New formulation, 6, 1%

Biosimilar, 5, 1%

Regenerative medicine, 4, 1%

New indication of regenerative

medicine, 3, 0%

Unknown, 2, 0%

Projects by Planned filing Category

51, 8%43, 6%

577, 86%

3, 0%Development Status

Approved

Filed

In-development

Unknown

425, 63%

249, 37%

Simultaneous Submission planned*

1 YES

2 NO

* Simultaneous submission: defined as filing within 3 months after US or EU filing

New MOA, 487, 72%

Not new MOA, 187,

28%

EFPIA + PhRMA 674 projects

12

Clinical Studies and Development Plan

Therapeutic Area for Projects in FY2018

Key findings : Oncology is a major focused area and the proportion of projects regarding oncology accounts for 55% of the total projects in FY2018.

370, 55%

89, 13%

32, 5%

27, 4%

18, 3%

16, 2%

16, 2% 15, 2%

14, 2%

10, 1%

9, 1%9, 1%

5, 1%

4, 1%

3, 0%

37, 5%

Oncology

CV/Med/Hormon

CNS/PN

Anti bacteria/Virus/Vaccine

Alzheimer

Sensoria

Respiratory

Allergy

Digestive

Regenerative medicine

Blood product

Immunosuppressant

Biologics/Biosimilar

Urinary

Parkinson disease

Others

13

Plan for SAKIGAKE/Breakthrough(BT)/PRIME

Key findings : In FY2018, the number of projects with plan for SAKIGAKE designation is 31 (5%). The number of projects with BT planned is highest (14%) among three expedited programs.

Plan for SAKIGAKE

Plan for BT

Plan for PRIME

38, 7%

31, 5%

489, 93%

643, 95%

0 200 400 600 800

2017

2018

No

Yes

71, 13%

96, 14%

452, 86%

578, 86%

4, 1%

0 200 400 600

2017

2018

Unknown

No

Yes

57, 11%

35, 5%

466, 88%

639, 95%

4, 1%

0 200 400 600 800

2017

2018

Unknown

No

Yes

14

Plan for Pediatric Development

Key findings : 18% of projects have a plan for the development for pediatric patients. Roughly 60% of projects are planning to develop for pediatric patients following the development for adults.

Metabolic 17

CNS 17

Oncology 10

CV 9

Allergy 8

Digestive 8

Respiratory 7

Blood product 7

Anti-virus 5

Vaccine 4

Hormone 3

Regenerative 3

Anti-bacterial 2

Skin 2

Sensoria 2

Urinary 2

Contrast agent 1

Others 16

Planning or developing,

123, 18%

No, 551, 82%

Simultaneously, 51, 41%

Following adults, 72, 59%

Timing of Development Development plan for pediatric patients

Therapeutic Area

15

Plan for Pediatric Development

Key findings : For the majority of projects, development for pediatric patients are considered in the same timeframe as global development. The survey results also indicate that of projects for which clinical data package has been determined, participating global pediatric clinical program is predominant strategy.

59

13

0

0 10 20 30 40 50 60 70

Around the same time as overseas

During reexamination period

After reexamination period

Decision Timing for Pediatric Development- Following development in adults - (N= 72 projects)

Clinical data package for pediatric development (N=123 projects)65

3

9

0

12

30

4

0 20 40 60

Only MRCT inc.J

MRCT inc.J and Japan PK trial

MRCT inc.J and Japan trial(s) (exc,PK)

Japan PK and other Japan trial(s)

Only other Japan trial(s)(exc.PK)

TBD

Others

16

PMDA Consultation for MRCT

Key findings : PMDA consultation or Pre-meeting were held before starting MRCT at the rate of 54% (PMDA consultation: 42%, Pre-meeting: 12%).

PMDA consultation,

252, 42%

Pre-meeting, 72, 12%

No meeting, 280, 46%

PMDA consultation, 75, 23%

Pre-meeting, 41, 13%


Oncology

PMDA consultation,

192, 51%

Pre-meeting, 30, 8%


Late Phase (P2/3, P3)

1

15

31

40

0 10 20 30 40 50

Unknown

No change

Japan specific protocolamendment

MRCT protocol change

9

39

87

226

0 20 40 60 80 100 120 140

Actual change of number ofJapanese

Request for change of numberof Japanese

Request for Protocol change(except No of Japanese)

PMDA consultation pertinentto Study Protocol

18

Free comments• Internal Actions to minimize submission lag

– Development plan for assuming simultaneous filing– Improvement of CTD preparation process– Good communication with global from early stage

• Difficulties for SAKIGAKE designation– Conflict with expedited scheme in US/EU– Human resources for JNDA preparation– Understanding and getting support from global– Unclear benefit to drug pricing system

Overall findings and discussionsThe followings are considered as the background to lead the result;

- It is necessary to secure additional time and resources for JNDA preparation.

- NDA timing in US/EU is decided first and then decide JNDA timing. For “Japan First” and “ on the Same Day” submission in Japan, tough negotiation between global is needed to get agreement to give priority to Japan

- Up-to 3 months lag is considered “simultaneous filling” internally and 3 months is reasonable for JNDA preparation.

20

PMS for Approved Products in FY2018（N:22 companies [EFPIA:10, PhRMA: 12])

N=59 (Product)

44(75%)

15(25%)

Product with PMS

YesNo

0

2

4

6

8

Office 2 Office 4 Office 5

11

13

71

1

Products without PMS

New Dosage

New Indication

New Combo

NCE

N=15 (Product)

Key findings : PMS is conducted for almost all of NCE products. Products without PMS are predominately those approved for new indication.

0

5

10

15

20

4 4 4 3 31 2

1

97

1

11

3

2

3

Type of PMS by PMDA Review Office

Post-MarketingDB Survey

Specific DrugUse Survey

Drug Use Survey

N=49 (PMS)

40

3

1

38

5

1

1 Survey

2 surveys

3 surveys

Number of PMS per Product

FY2017 (N=44)

FY2018 (N=44)

21

PMS

Details of PMS(Drug Use Survey and Specific Drug Use Survey : N = 40 )

0 5 10 15 20 25 30

～300

300～500

500～1000

1000～2000

2000～3000

NA

27

5

4

1

1

2

Number of Patients per PMS

0 2 4 6 8 10 12 14 16

～1Y

1Y～2Y

2Y～3Y

3Y～5Y

＞5Y

NA

1

14

14

5

4

2

Enrollment Period

0 5 10 15 20 25

<100M Yen

100～300M Yen

300～500M Yen

>500M Yen

5

22

11

2

0 5 10 15 20 25 30 35

Not outsourced

<100M Yen

100～300 M Yen

Individual PMS cost not available

31

5

3

1

Cost of Outsourced PMS Monitoring

Key findings：

• Less than 300 patients in size, 6 month to 1 year observation period and 1-3Y year enrollment period are most frequently seen among all PMS.

• PMS with cost of 100 – 300 M Yen marked highest number and majority costs more than 100 M Yen.

Cost of PMS (excluding monitoring cost)

0 5 10 15 20

～24W(6M)

6M～52W(1Y)

1Y～2Y

2Y～3Y

>3Y

7

19

5

3

6

Observation Period per Patient

23

Post-Marketing Database SurveyReason for Database Survey Planned

26, 65%

1, 2%

1, 3%12, 30%

Reason for DB Survey Not Considered (N=40) Data of iterest can not be collected through DB

DB is not necessarily suitable to evaluate specific risk

Lack of understanding about usefulness about DB within the company

Others (not applicalbe due to all-case survey, HRD Survey)

Other

Registry

JMDC

MDV

MID-NET

1

2

1

4

1

Database used for DB Survey

Key findings：

• The proportion of DB survey per product with PMS increased from 7% (4/54) in FY2017 to 15% (9/59) in FY2018.

• The advantage for DB survey recognized predominantly is that DB could be suitable for some specific diseases and to evaluate specific risks

• Among reasons why DB was no considered, the majority is that DB does not necessarily suitable to collect data of interest.

6

1

1

1

9

Other

Total

DB enables comaparison, to gain experience to DB survey, Suitable DB available

for the disease and to evaluate risk

To gain experience to DB survey, suitable DB available for the disease and to

evaluate risk, cost saving

Suitable DB available for the disease and to evaluate risk

24

PhRMA+EFPIAUtilization of Expedited Program Approved in PMDA in FY2018 : One product/One line

In Japan, first case of Sakigake, two Conditional Early Approval and many Priority Review as well as Orphan drugs were utilized. Expedited program is widely granted in the US.

PMDA (N=45) FDA (N=45) EMA (N=42)

SakigakeCondi-tional

Early Approval

Priority Review

OrphanBreak-

through Desig-nation

Accele-rated Approval

Fast TrackPriority Review

Orphan PRIME

Condi-tional Marketing Authori-zation

Accele-rated Assess-

ment

Excep-tional Circum-stances

Orphan

1 Sakigake PR Orphan BTD FT PR Orphan Orphan

2 PR Orphan BTD AA PR Orphan CMA Orphan

3 PR Orphan BTD PR Orphan PRM Orphan

4 PR Orphan BTD PR Orphan Orphan

5 PR Orphan BTD PR Orphan

6 PR Orphan BTD PR Orphan

7 PR Orphan BTD

8 PR Orphan PR

9 PR Orphan PR

10 PR Orphan PR

11 PR Orphan FT Orphan AA Orphan

12 PR Orphan Orphan Orphan

13 PR Orphan Orphan Orphan

14 PR Orphan

15 PR Orphan Orphan NA NA NA NA NA

16 PR Orphan

17 PR BTD FT PR AA

18 PR BTD PR

19 PR BTD PR

20 PR BTD PR

21 CEA PR BTD AA NA NA NA NA NA

22 CEA PR BTD AA Orphan CMA

23 PR PR Orphan

24 PR PR

25 PR AA

26 Orphan

27 BTD PR

28 BTD PR

29 PR

30 PR

31 PR

32 FT

33

34

35

36

37

38 Orphan

39

40 NA NA NA NA NA

41

42

43

44

45

1 2 25 17 15 4 4 20 13 1 2 2 0 7

9

Submission/Approval Gap of 18 NMEs (New Molecular Entities ) 3

119.7

3

46.4

1

39.7

1

34.2

1

31

18

53.4

70.8

4

17.9

6.8

6.6

4

5.4

16

5.1

1

4.4

2

4.4

8

10.3

1

2.1

1

1.5

1.3

0.5

0.5

46

12

8

14

10.3

3

13

8.5

8

10

3

8

8

7.8

8

12

3.4

10.1

9.9

11.1

12

17

11.7

4.8

3.9

4

11

11.9

33

24.6

8

14

7.3

14

11.8

5

11

10.3

12

14

11.1

11

7.7

10

6

12.7

10.1

0 12 24 36 48 60 72 84 96

FDA

EMA

PMDA

FDA

EMA

PMDA

FDA

EMA

PMDA

FDA

EMA

PMDA

FDA

EMA

PMDA

FDA

EMA

PMDA

FDA

EMA

PMDA

FDA

EMA

PMDA

FDA

EMA

PMDA

FDA

EMA

PMDA

FDA

EMA

PMDA

FDA

EMA

PMDA

FDA

EMA

PMDA

FDA

EMA

PMDA

FDA

EMA

PMDA

FDA

EMA

PMDA

FDA

EMA

PMDA

FDA

EMA

PMDA

12

34

56

78

91

01

11

21

31

41

51

61

71

8

Submission Gap

Review Time

Review on-going

132

10

The timing when to submit filing seems to contribute the approval timing. The review time of PMDA is almost same as one in FDA and EMA, some are faster than other HAs.

Submission/Approval Gap of 24 LCMs (Life Cycle Managements) 27.8

42.70.1

34.5

1.026.2

118.4

2.0

20.1

3.716

914.3

11.511.9

0.911.2

16.3

6.21

6.50.4

4.9

2.53.3

13

0.92.9

0.11.1

0.2

1

0.30.6

20.5

1

1.5

0.40.4

2.4

14.515.5

108

8.59.9

8.310.7

6.07.0

7.410

119.9

10.014.0

3.912.8

13.110.7

69

11.12.5

39.9

9.98.7

11.17

911.1

2113

9

77.9

4.95.7

4.410

11.96

147.2

4.79.2

11.55.8

7.48.8

1087.4

69.7

7.512

1411.8

913

8.76

117.8

4.8

0 12 24 36 48 60 72

FDA

EMA

PMDA

FDA

EMA

PMDA

FDA

EMA

PMDA

FDA

EMA

PMDA

FDA

EMA

PMDA

FDA

EMA

PMDA

FDA

EMA

PMDA

FDA

EMA

PMDA

FDA

EMA

PMDA

FDA

EMA

PMDA

FDA

EMA

PMDA

FDA

EMA

PMDA

FDA

EMA

PMDA

FDA

EMA

PMDA

FDA

EMA

PMDA

FDA

EMA

PMDA

FDA

EMA

PMDA

FDA

EMA

PMDA

FDA

EMA

PMDA

FDA

EMA

PMDA

FDA

EMA

PMDA

FDA

EMA

PMDA

FDA

EMA

PMDA

FDA

EMA

PMDA

12

34

56

78

91

01

11

21

31

41

51

61

71

81

92

02

12

22

32

4

Submission Gap

Review Time

Review on-going

300

285

The timing when to submit filing seems to contribute the approval timing. The review time of PMDA is almost same as one in FDA and EMA, some are faster than other HAs.

11

Number of Clinical Studies (Global/ Domestic)

Key findings : The total number of studies in FY2018 was 792 and the ratio of Global studies was 76% in FY2018.

352

24

63

33

4

24

67

54

4

14

8

1

8

89

0 100 200 300 400 500

Ph3

Ph2/3

Ph2

Ph2b

Ph2a

Ph1/2

Ph1

Global vs Domestic by Development Phase

Global

Domestic

364435

493

604

184 189 175 188

548624

668

792

0

100

200

300

400

500

600

700

800

900

FY2015 FY2016 FY2017 FY2018

Global vs Domestic from FY2015 to FY2018

Global

Domestic

Total

(24%)

(76%)

17

EFPIA + PhRMA 792 studies

Type of PMS for Approved Products

Key findings：

• Regarding Drug Use Survey and Specific Drug Use Survey, majority of them are accepted as planned.

• Though n is small, most of DB Survey are not initially considered but recommended by PMDA.

• Though n is small, the proportion of All-case surveys for products reviewed by Office 4 is relatively high (7/16; 43%).

1

15

3

6

2

14

16

1

0 10 20

Drug Use Survey (n=18)

Specific Drug Use Survey(n=22)

Post-Marketing DB Survey(n=9)

Background for PMS Type Selected

Agreed with PMDA as planned

Initially submitted to conduct no PMS, consequentlyconcluded to conduct PMS after discussion with PMDA

Initailly, Drug Use Survey was considered, However, afterdiscussion with PMDA, changed to DB Survey

Others

N=49 (PMS)

0

5

10

15

20

1 1 1

72 31 1

4

9

11

34

1

All-Case Survey by PMDA Review Office

No(69%)

Yes(31%)

N=49 (PMS)

22

Japan First , 9, 4% Same Day,

6, 3%

Within 6M, 17, 8%

More than 6M, 45,

22%

Within 3 M,129, 63%

95

4

45

9

10

27

0 20 40 60 80 100

Internal criterion of simultaneous JNDA iswithin 3M from US/EU

Delay of starting Japan development

Business decision

Consider timing of Inquiry from Agencies

Japan specific reason

Not aiming forsimultaneous development

Within 3 M (n=129)

# of planned JNDA until end of March 2021 : 206/674 projects, 31%

Submission lag between US/EU

- J-CTD preparation (7)- PMDA’s request that affects to

JNDA timing (2)- Long term study in Japanese

(2)- Additional analysis (1)- Other (1)

- Internal decision (1)

18

14

28

5

28

15

0 20 40 60 80 100

More than 3M (n=62)

19

- PMDA’s request that affects to JNDA timing (17)- P1 study in Japanese (4)- Additional study for

licensing-in product (4)- Other study (3)- Not accepted result of OS

and surrogate endpoint (3)- Additional analysis (3)- Others (6)

- Internal decision (3)- J-CTD preparation (2)- Others (6)

PhRMA-EFPIA Joint Survey 2019• Review Period

– Review time for new drug approvals in FY2018

– Submission/approval gap

– Utilization of expedited program

• Clinical Studies and Development Plan

– Projects ongoing in FY2018

– Filing gap

– Global and local studies ongoing in FY2018

– Interaction with the agency for global studies

• PMS

– PMS in approved new drugs

Companies involved:PhRMA (12 companies)

• Abbvie, Alexion, Amgen Astellas BioPharma, Biogen Japan, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, MSD, Mundipharma, Pfizer, and Gilead Sciences

EFPIA (17 companies)

• Actelion, AstraZeneca, Bayer, CHUGAI, CSL Behring, Ferring, GlaxoSmithKline, Janssen, LEO, Lundbeck, Merck Biopharma, Boehringer Ingelheim, Novartis, Novo Nordisk, Sanofi, Shire, and UCB

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Submission lag between US/EU Free comments...2019/09/02 ·...

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