34

9

20

21

73

13

98

10

61

42

2

2

0

1

36

5

0

1

14

23

3

3

6

9

84

17

157

17

158

160

0% 20% 40% 60% 80% 100%

Sensory organ agents

Urogenital/anal organ agents

Antibiotics

Cardiovascular agents

CNS agents

Hormones

Chemotherapeutics

Digestive organ agents

Agents affecting metabolism

Biological preparations

11

16

47

32

103

328

393

38

431

0

1

12

25

39

51

81

9

90

118

42

78

128

333

313

636

10

646

0% 20% 40% 60% 80% 100%

Enzymes

Hormones

Protein

Antibody

Non-small molecules

Small molecules

Other ADR

Clinically significant ADR

All

0% 20% 40% 60% 80% 100%

Other ADR

Clinically significant ADR

All（clinically significant + others）

single 2 weeks 4 weeks 13 weeks 26 weeks 52 weeks 104 weeksMinimal duration of administration periods

Predictable = Detected in nonclinical studies + Predictable from mechanism of action

0

10

20

30

40

50

60

70

80

90

100 （％）

Materials and Methods

234 new molecular entities approved in Japan from 2001 to 2010

Exclude vaccines & anti-cancer drugs

Choose drugs with ADR of incidence of 5% or more based on package inserts in Japan

134 drugs and 1202 ADR

Kazuichi Nakamura, Shigeru Hisada, Takako Ohkura, Yasuo Yoneta, Kenichi Hattori, Yamato Ogino, Chihiro Tamaki, Yoshiharu Takashima, Daisaku Yasugi, Masamichi Hashiba, Misa Matsumura, and Takashi Nagayama

Concordance between Non-Clinical and Clinical Toxicity Data Determined by a Survey of Approved Pharmaceuticals in Japan

Non-Clinical Evaluation Expert Committee, Drug Evaluation Committee, Japan Pharmaceutical Manufacturers Association, Tokyo, Japan

Objective

Concordance analysis Pick up nonclinical findings corresponding to the

above clinical ADR based on NDA dossiers and PMDA*’s review reports

Detected in nonclinical studies

NOT detected in nonclinical studies

Predictable from mechanism of action

Associated with other ADR

Associated with primary disease

Predictable from available information

* Pharmaceuticals and Medical Devices Agency

Non-predictable

Basic Profiles of Drugs Analyzed

Concordance Analysis Based on

Severity of Clinical ADR and Drug Classes

Overall concordance was 36%, higher in the clinically significant ADR. Non-small molecule drugs,

especially enzymes and antibodies, showed lower concordance than small molecule drugs.

Concordance Analysis Based on

Target Organs of ADR

Small molecules Non-small molecules

Musculoskeletal, respiratory, nose & neurology ADR showed lower concordance in small molecule

drugs. Non-small molecule drugs showed lower concordance than small molecule drugs in many

organs.

Musculoskeletal

Respiratory

Nose

Others

Neurology

Faucal/Oral

Systemic

Metabolic

Urinary

Skin

Cardiovascular

Eyes

Hepatobiliary

Blood

Gastrointestinal

Infection

Application sites

Musculoskeletal

Cardiovascular

Neurology

Systemic

Urinary

Hepatobiliary

Gastrointestinal

Skin

Respiratory

Nose

Faucal/Oral

Metabolic

Infection

Blood

Others

Application sites

Eyes

Organs with concordance lower than 40% are highlighted.

Concordance Analysis Based on

Therapeutic Category in Japan

Biological preparations & agents affecting metabolism showed lower concordance.

Based on the Japan Standard Commodity Classification (JSCC). Therapeutic category incl. >5 agents and >10 AE are shown.

Concordance Analysis Based on

Route of Administration

Small molecules

*Subcutaneous also includes percutaneous and intramuscular routes.

Non-small molecules

Oral

Intravenous

Subcutaneous*

Ocular/ Intravitreal

In small molecule drugs, oral administration showed lower concordance than intravenous

administration. Subcutaneous administration showed higher concordance than

intravenous administration in small and non-small molecule drugs.

There is no oral route drug.

Exposure Ratio of Animals to Human

Exposure ratio; Animal exposure/Human exposure

Approximately 70% of animal toxicities were observed at less than 10 times exposure

(Cmax and AUC) in human.

Exposure Ratio (Cmax, 82 ADR in 35 drugs)

0% 20% 40% 60% 80% 100%

Other ADR (72)

Clinically significant ADR (10)

All (82)

< 1

1 to 10

10 to 30

30 to 100

>= 100

Exposure Ratio (AUC, 178 ADR in 60 drugs)

0% 20% 40% 60% 80% 100%

Other ADR (163)

Clinically significant ADR (15)

All (178)

< 1

1 to 10

10 to 30

30 to 100

>= 100

Conclusions

2278

In

cid

en

ce o

f A

DR

0% 20% 40% 60% 80% 100%

>50%30-50%20-30%10-20%

5-10%All

Gastrointestinal Neurology Hepatobiliary Blood SkinSystemic Cardiovascular Eyes Muscloskeletal Faucal/OralMetabolic Urinary Infection Respiratory Others

Predictability Analysis of Individual ADR

Pre

dic

tabili

ty

This is the latest study investigating the concordance between adverse drug

reactions (ADR) and animal toxicities for marketed drugs approved in the first decade

of the 21st century in Japan. Similar studies1,2) were conducted in 1990’s. Since then,

however, the drug development situation has dramatically changed; for example,

many biotechnology-derived pharmaceuticals have emerged in the market. .

The objective of this study is to improve the safety evaluation of pharmaceuticals by

considering the concordance. It might be necessary to find solutions in non-clinical

and clinical studies especially as for poor concordant parameters. The present

concordance analysis study should provide new aspects of drug safety evaluation. .

1) JPMA non-clinical evaluation expert committee report No. 65 (1994)

2) Olson H. et al. Regul. Toxi. Pharmacol. 32, 56-67 (2000)

Route of Administration Drug Class

Therapeutic Category in Japan

Based on the Japan Standard Commodity Classification (JSCC).

Oral

Intravenous

Subcutaneous

Intramuscular

Eye drops

Percutaneous

Inhalation

Others

Other agents affecting metabolism

Chemotherapeutics

CNS agents

Biological preparations

Cardiovascular agents

Hormones

Sensory organ agents

Antibiotics

Others

Small molecule

Antibody

Protein

Hormones

Enzymes

Others

• Overall concordance value between human ADR and animal toxicities

was 36%. The value was higher in clinically significant ADR and high

incidence ADR than other ADR and low incidence ADR respectively.

Oral drugs showed a lower value in comparison with other drugs.

• Approximately 70% of animal toxicities were observed at less than 10

times exposure (Cmax and AUC) in human. More than 80% of animal

toxicities were observed within 1-month studies.

• Some ADR (blood pressure increase, triglyceride increase etc.),

parameters of which can be measured in animals, showed relatively low

predictability. Further studies are expected to elucidate this point.

ADR concordance was positively correlated with incidence of ADR.

Blood, systemic, and urinary ADR were mainly observed in higher incidence ADR group.

Gastrointestinal and hepatobiliary ADR were rare in more than 50% incidence group. Neurology

ADR is observed over wide range of incidence.

More than 80% of animal toxicities were observed within 1 month-studies.

Approximately 5% of clinically significant ADR needed 104-week study for the detection

of non-clinical findings. These ADR were related to decrease of leukocytes/neutrophiles.

+ Associated with other ADR + Associated with primary desease

Low

predictability

Measurable both in human and animals

ADR which are difficult to observe directly in animals (e.g. subjective symptoms) generally

showed lower predictability and vice versa. However, some parameters measurable both in

human and animals, such as triglyceride increase and blood pressure increase, also showed

low predictability.

Concordance Analysis Based on Incidence of ADR

Administration Periods for Concordant ADR