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Annals of Oncology
14.
15.
16.
17.
18.
19.
20.
nasopharyngeal carcinoma from endemic regions of China. Cancer 2013; 119:
2230–2238.
Chen L, Hu CS, Chen XZ et al. Concurrent chemoradiotherapy plus adjuvant
chemotherapy versus concurrent chemoradiotherapy alone in patients with
locoregionally advanced nasopharyngeal carcinoma: a phase 3 multicentre
randomised controlled trial. Lancet Oncol 2012; 13: 163–171.
Parmar MK, Torri V, Stewart L. Extracting summary statistics to perform metaanalyses of the published literature for survival endpoints. Stat Med 1998; 17:
2815–2834.
Chen QY, Wen YF, Guo L et al. Concurrent chemoradiotherapy vs radiotherapy
alone in stage II nasopharyngeal carcinoma: phase III randomized trial. J Natl
Cancer Inst 2011; 103: 1761–1770.
Lin JC, Jan JS, Hsu CY et al. Phase III study of concurrent chemoradiotherapy
versus radiotherapy alone for advanced nasopharyngeal carcinoma: positive effect
on overall and progression-free survival. J Clin Oncol 2003; 21: 631–637.
Baujat B, Audry H, Bourhis J et al. Chemotherapy in locally advanced
nasopharyngeal carcinoma: an individual patient data meta-analysis of eight
randomized trials and 1753 patients. Int J Radiat Oncol Biol Phys 2006; 64:
47–56.
Chan AT, Teo PM, Ngan RK et al. Concurrent chemotherapy-radiotherapy
compared with radiotherapy alone in locoregionally advanced nasopharyngeal
carcinoma: progression-free survival analysis of a phase III randomized trial. J Clin
Oncol 2002; 20: 2038–2044.
Chan AT, Leung SF, Ngan RK et al. Overall survival after concurrent cisplatinradiotherapy compared with radiotherapy alone in locoregionally advanced
nasopharyngeal carcinoma. J Natl Cancer Inst 2005; 97: 536–539.
21. Zhang L, Zhao C, Peng PJ et al. Phase III study comparing standard radiotherapy with
or without weekly oxaliplatin in treatment of locoregionally advanced nasopharyngeal
carcinoma: preliminary results. J Clin Oncol 2005; 23: 8461–8468.
22. Wu X, Huang PY, Peng PJ et al. Long-term follow-up of a phase III study
comparing radiotherapy with or without weekly oxaliplatin for locoregionally
advanced nasopharyngeal carcinoma. Ann Oncol 2013; 24: 2131–2136.
23. Blanchard P, Hill C, Guihenneuc-Jouyaux C et al. Mixed treatment comparison
meta-analysis of altered fractionated radiotherapy and chemotherapy in head and
neck cancer. J Clin Epidemiol 2011; 64: 985–992.
24. Jacobs C, Lyman G, Velez-Garcia E et al. A phase III randomized study comparing
cisplatin and fluorouracil as single agents and in combination for advanced
squamous cell carcinoma of the head and neck. J Clin Oncol 1992; 10:
257–263.
25. Chan AT, Gregoire V, Lefebvre JL et al. Nasopharyngeal cancer: EHNS-ESMOESTRO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann
Oncol 2012; 23(Suppl 7): vii83–85.
26. Cheng SH, Tsai SY, Yen KL et al. Prognostic significance of parapharyngeal space
venous plexus and marrow involvement: potential landmarks of dissemination for
stage I-III nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 2005; 61:
456–465.
27. Leung SF, Chan KC, Ma BB et al. Plasma Epstein-Barr viral DNA load at midpoint
of radiotherapy course predicts outcome in advanced-stage nasopharyngeal
carcinoma. Ann Oncol 2014; 25: 1204–1208.
Annals of Oncology 26: 211–216, 2015
doi:10.1093/annonc/mdu500
Published online 30 October 2014
Acceptance of surrogate end points in clinical trials
supporting approval of drugs for cancer treatment by
the Japanese regulatory agency
H. Maeda1,2* & T. Kurokawa1
1
Graduate School of Pharmaceutical Sciences, Keio University, Tokyo; 2Astellas Pharma, Inc., Tokyo, Japan
Received 3 July 2014; revised 24 August 2014 and 12 September 2014; accepted 15 October 2014
Background: This study investigated the historic use of different end points to support approval of drugs for cancer
treatment in Japan.
Patients and methods: Anticancer drugs approved between April 2001 and April 2014 were comprehensively investigated using publicly available information.
Results: Before the revision of the guideline for oncology drugs in April 2006 in Japan, >80% of end points supporting
approval were response rate and overall survival (OS) was not frequent. After the revision of the guideline in Japan, using
OS in pivotal clinical trials applied for approval increased to more than approximately one-third of oncology drugs,
although trials with an end point of response rate decreased. Regarding drugs for major cancers including non-small-cell
lung cancer, gastric cancer, colorectal cancer, and breast cancer, survival was used as an end point in 44.0%, whereas
surrogate end points were used in 56.0%. Exploration of potential factors for using surrogate end points other than
survival carried out through determinations of
*Correspondence to: Mr Hideki Maeda, Drug Development and Regulatory Science,
Graduate School of Pharmaceutical Sciences, Keio University, 1-5-30 Shibakoen,
Minato-ku, Tokyo 105-8512, Japan . Tel: +81-3-3434-6241; Fax: +81-3-5400-2649;
E-mail: hideki.maeda@astellas.com
© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
All rights reserved. For permissions, please email: journals.permissions@oup.com.
original articles
Annals of Oncology
odds ratios and 95% confidence intervals identified ‘orphan drug designation in Japan’ and ‘accelerated approval by the
U.S. Food and Drug Administration’ as significant factors.
Conclusions: The revised guideline for oncology drugs in Japan requires the results of phase 3 studies with survival as
an end point at the time of new drug application at least for major cancers. The regulatory agency in Japan also accepts
surrogate end points as end points supporting approval besides survival; however, the number of surrogate end points
has decreased after the revision of the guideline. We consider that accepting surrogate end points in the Japanese regulatory systems is important to approve oncology drugs quickly in Japan.
Key words: drugs for cancer treatment, Japan, oncology drugs, PMDA, surrogate end point, survival
introduction
methods
The guideline of methods for the clinical evaluation of anticancer drugs issued in February 1991 represents the first regulation
for the clinical development of anticancer drugs in Japan [1]. In
the past, the regulatory agency would accept the results of phase
2 studies that mainly used a response rate as an end point in accordance with this guideline and grant approval for anticancer
drugs. However, the guideline for anticancer drugs was revised
[2], and was implemented in April 2006. The revised guideline
describes non-small-cell lung cancer (NSCLC), gastric cancer
(GC), colorectal cancer (CRC), and breast cancer (BC) as examples of major cancers from which many patients suffer, and
requires the results from phase 3 studies with life-prolonging
effects, such as overall survival (OS) as an end point, to be submitted at the time of application, at least for drugs indicated for
major cancers.
OS is the gold standard for a ‘hard end point’ in clinical studies
in the area of oncology [3]. Not only the Pharmaceuticals and
Medical Devices Agency (PMDA) in Japan, but also regulatory
agencies in developed countries outside Japan, such as the Food
and Drug Administration (FDA) in the USA and the European
Medicines Agency (EMA), currently demand that OS is used as
an end point for clinical pivotal studies to be included in the clinical data package at the time of New Drug Application (NDA) for
approval of an oncology drug [4–6]. However, the problem with
conducting a clinical study using OS is that the size of study is
increased compared with a study using other end points, requiring a number of years until the study ends. Drug development
is a long and costly process, typically taking 15 years and $1
billion to shepherd a drug through the initial discovery, clinical
testing, and regulatory approval [7]. Inclusion of surrogate end
points and shorter end points will ensure faster clinical trials in
oncology and faster launch of drugs for cancer, and will therefore provide numerous benefit to patients.
There have been no studies on end points used in clinical
studies supporting approval of oncology drugs in Japan. This
study comprehensively investigated end points that have been
used in pivotal clinical studies for the approval of oncology
drugs in Japan, and examined factors that potentially influence
the acceptance of surrogate end points as an approval condition
set by the PMDA, the Japanese regulatory agency.
selection of drugs for cancer treatment
This study included all anticancer drugs approved by the PMDA for systemic
therapy of cancer treatment. Investigations were carried out on drugs
approved from April 2001 or later and approved by April 2014. We collected
data for anticancer drugs only; drugs for supportive or palliative care were
not included. Approvals for new formulations of drugs for comparable indications were excluded.
data collection
Data were collected from the databases available to public in the PMDA
website (http://www.pmda.go.jp/english/index.html). Each indication was
counted for each drug, including indications approved at the same time, as
long as substantive data with pivotal clinical trials for each indication.
Documents were also used as references regarding drugs discussed in the
special committee (http://www.mhlw.go.jp/stf/seisakunitsuite/bunya/kenkou_
iryou/iyakuhin/kaihatsuyousei/index.html; in Japanese), and drugs for the
public knowledge-based application (http://www.mhlw.go.jp/bunya/iryouhoken/
topics/110202-01.html; in Japanese).
For end point evaluation, only one pivotal trial (the largest or most relevant trial) was considered for each indication. Additionally, when the
primary study end point was multiple, and multiple end points met statistical
criteria, the end point with highest priority was taken for this analysis,
according to the following hierarchy: survival; symptom; time to event ( progression-free survival [PFS], time to progression, and time to recurrence);
and response rate. For example, if OS did not show a significant difference
for an approved drug, but PFS did, then the drug was regarded as approved
on the basis of PFS. Response rates also included hematological response, in
patients with hematologic malignancy. Information on the US Regulatory
measures that applied to drugs for NDA review was collected from the FDA
website (http://www.accessdata.fda.gov/scripts/cder/drugsatfda/).
statistical methods
We used Fisher’s exact test for a 2-by-2 contingency table to compare distributions of categorical attributes. To compare potential factors for using surrogate end points, we estimated the odds ratio (OR) and 95% confidence
interval (CI).
results
historic use of different end points
Table 1 summarizes end points that were used to support approval of oncology drugs in Japan before and after the guideline
revision in April 2006. End points used to support approval
were defined as those used in pivotal clinical trials conducted at
the time of NDA. Before the revision of the guideline, >80% of
end points to support approval were response rate. After the
 | Maeda and Kurokawa
Volume 26 | No. 1 | January 2015
original articles
Annals of Oncology
Table 1. Changes in end points supporting approval of oncology
drugs before and after the revision of the guideline for oncology
drugs in Japan
End point
Survival
Response rate
Progression-free survival
Time to progression
Disease-free survival
Quality of life
Patient-reported outcomes
Other end points
Total
Before the
guideline
revisiona
N
%
After the
guideline
revisionb
N
%
2
26
0
2
1
0
0
1
32
29
28
15
5
2
0
0
4
83
6.3
81.3
0.0
6.3
3.1
0.0
0.0
3.1
100.0
34.9
33.7
18.1
6.0
2.4
0.0
0.0
4.8
100.0
a
Between the approval of drugs from April 2001 and new drug
application by March 2006.
b
Between new drug application from April 2006 and the approval of
drugs by April 2014.
revision, survival increased to the most frequently used end
point at 34.9%, followed by response rate at 33.7%. We defined
end points other than survival as the surrogate end points. With
a 2-by-2 table, we carried out comparison before and after the
revision of the guideline, and found significant difference in
using surrogate end points between before and after revision
(P = 0.002, Fisher’s exact test, supplementary Table S1 and
Figure S1, available at Annals of Oncology online).
oncology drugs after the revision of the guideline
Drugs for cancer submitted for approval after 1 April 2006
(the day on which the revised guideline to methods for the clinical evaluation of anticancer drugs came into effect) were investigated in more detail. By 30 April 2014, a total of 55 drugs had
been approved in Japan for 83 oncology indications (supplementary Table S2 and Figure S2, available at Annals of Oncology
online). Table 2 presents the results of aggregation of 83 indications. Of these indications, 31 were approved through the
initial NDA (iNDA), and 52 through the supplemental NDA
(sNDA). Of those in the iNDA, indications for sunitinib
(renal cell carcinoma and gastrointestinal tumor) and dasatinib
(chronic myelogenous leukemia and Philadelphia-positive acute
lymphoblastic leukemia) were approved at the same time, so
each drug was regarded as approved through two separate
iNDAs. By mechanism of action, the largest number of indications was approved for molecularly targeted drugs, at ∼50%, followed by cytotoxic drugs at 42%. Drugs belonging to the other
drugs were vaccines and radioactive agents. As for methods of
application, the largest number of drugs went through priority
review designation at 31.3%. Regarding types of development,
bridging strategy accounted for >50%.
Table 3 reports the cancer types of these 83 indications.
NSCLC, GC, CRC, and BC, which were regarded as major
Volume 26 | No. 1 | January 2015
Table 2. Tabulation of approved drugs for cancer between 2006 and
2014 in Japan
Items
Type of NDA
iNDA
sNDA
Mechanism of action
Molecularly targeted drugs
Cytotoxic drugsa
Hormonal drugs
Other drugs
Types of application in Japan
Priority review/expedited reviews
Normal application
Orphan drug designation
Public knowledge-based application
Type of development
Bridgingb
Catch upc
No clinical studies by companies in Japand
Simultaneouse
Full developmentf
Post-marketing commitment
All case investigation after approval
Others
Nothing
N
%
31
52
37.3
62.7
41
35
4
3
49.4
42.2
4.8
3.6
26
25
17
15
31.3
30.1
20.5
18.1
47
15
15
3
3
56.6
18.1
18.1
3.6
3.6
31
4
48
37.3
4.8
57.8
iNDA, initial new drug application; sNDA, supplemental NDA.
Includes anti-metabolites, alkylating agents, anti-microtubule
agents, and platinum.
b
Strategy with pivotal studies conducted outside Japan and with a
bridging study in Japan.
c
Strategy in which a pivotal study was conducted as a global clinical
trial by the USA, European Union, and Asia including Japan after a
small-scale phase 1 study was completed in Japan.
d
Strategy with a public knowledge-based application system [8].
e
Strategy under simultaneous development carried out in the world
including Japan.
f
Strategy in which drugs were developed independently in Japan.
a
cancers in the revised guideline, accounted for 30.1% of the
whole. Indications with one or two drugs were classified as
‘Other solid tumors’ or ‘Other hematologic malignancies’ (supplementary Figure S3, available at Annals of Oncology online).
end points used to support the approval of
oncology drugs in Japan
We investigated the characteristics of drugs and indications
approved through clinical studies that used survival as an end
point supporting approval, and those approved through clinical
studies that used surrogate as an end point. Variables include
iNDA/sNDA, mode of action of drug, cancer type (major
cancer/non-major cancer), special applications in Japan
(orphan drugs, public knowledge-based application, priority
review, and review meetings on unapproved/off-label drugs),
limitation of indications, post-marketing commitment,
doi:10.1093/annonc/mdu500 | 
original articles
Annals of Oncology
Table 3. Types of cancer for approved oncology drugs in Japan
Tumor type
Major cancer (N = 25)
Breast cancer
Non-small-cell lung cancer
Colorectal cancer
Gastric cancer
Not major cancer (N = 58)
Renal cell carcinoma
Prostate cancer
Non-Hodgkin’s lymphoma
Ovarian cancer
Chronic myelogenous leukemia
Cervical cancer
Melanoma (phaeochromocytoma)
Multiple myeloma
Other solid tumorsa
Other hematologic malignanciesb
N
%
10
7
5
3
12.0
8.4
6.0
3.6
5
5
5
4
4
3
3
3
18
8
6.0
6.0
6.0
4.8
4.8
3.6
3.6
3.6
21.7
9.6
Drugs for cancer treatment submitted for approval after 1 April 2006
until 30 April 2014 were investigated.
a
Other solid tumors include head and neck cancer, hepatocellular
carcinoma, gastrointestinal stromal tumor, pancreatic cancer,
pancreatic neuroendocrine tumor, pediatric solid tumor, biliary
tract cancer, giant cell tumor, malignant glioma, mesothelioma,
subependymal giant cell astrocytoma, and urothelial cancer.
b
Other hematologic malignancies include chronic lymphocytic
leukemia, myelodysplastic syndrome, acute lymphatic leukemia,
chronic eosinophilic leukemia, cutaneous T-cell lymphoma, and
T-cell acute lymphoblastic leukemia.
developmental type, special applications for the FDA (fast track,
priority review/orphan, accelerated approval, and breakthrough
therapy designation), the FDA approval at approval in Japan,
and trial size of pivotal clinical studies. Among drugs for major
cancers, 44.0% were approved on the basis of studies that used
survival as the end point, whereas 56.0% used surrogate end
points. Fisher’s exact test was carried out to evaluate whether
survival was used as the end point in clinical studies involving
patients with major cancers and other types of cancers. No
significant difference was confirmed as a result (P = 0.318,
Figure 1). ORs and 95% CIs were determined for each risk
factor to evaluate whether surrogate end points were used
instead of survival (Figure 1). Among the potential factors,
‘orphan drug designation in Japan’ and ‘accelerated approval
designation in FDA’ were identified as factors leading to the use
of surrogate end points, with the lower limit of CI >1 for both
factors. In addition, ‘priority review in Japan’ and ‘bridging
strategy’ were identified as factors leading to the use of OS, with
the upper limit of CI <1 for both factors.
discussion
The previous Japanese guideline for oncology drugs stated that
phase 3 trials needed to be conducted after approval and
required only the protocol to be submitted at the time of
 | Maeda and Kurokawa
approval. In fact, however, almost no phase 3 trials were conducted after approval in Japan [8]. Therefore, the revised guideline in 2006 requires results of phase 3 trials for survival
benefits, especially in major cancers as mandatory. The purpose
of this study is to examine what end point the PMDA has
required for approval of oncology drugs after the revision of the
guideline, and to identify potential factors of surrogate end
points to be accepted by the PMDA.
Our study showed that using OS in pivotal clinical trials applied
for approval increased to more than approximately one-third of
drugs after the revision of guideline in Japan, whereas trials with
an end point of response rate decreased. On the other hand, about
two-thirds of drugs were found to have been approved with surrogate end points instead of OS in clinical trials. More than half of
drugs were approved on the basis of surrogate end points even for
cancers classified as major cancers in the guideline.
We identified ‘priority review designation in Japan’ and ‘bridging strategy’ as factors leading to the use of OS on the basis of an
upper limit of 95% CI of the OR <1. To interpret the result of ‘priority designation’, it is important to understand that the priority
review designation in Japan is granted after the NDA. We assume
that the PMDA tends to grant priority reviews for drugs for
which results with a big impact are obtained from studies that use
OS. ‘Bridging strategy’ was also a potential factor leading to the
use of OS. Only two indications with paclitaxel (Taxol, BristolMyers Squibb, US) out of 47 indications with ‘bridging strategy’
in our study include Japanese patients in pivotal trials, although
almost indications have no Japanese patients in pivotal trials.
A revised guideline accepts the results of pivotal trials with OS
conducted in abroad, because drugs can be provided to the
Japanese patients efficiently and speedily [2]. We suppose that the
extrapolation of robust OS data even outside Japan is acceptable
to the PMDA. However, there is no significant difference on the
use of OS between in simultaneous strategy with international
trials including Japan and in other strategies. We found that international clinical trials in the 18 simultaneous strategies had generally been conducted with a larger sample size (average 921
patients), primary end points were 10 PFSs, 4 response rates, 3
OSs, and 1 DFS. We suppose that there was no significant and
simple relationship between the use of OS and large scale trials.
Also, there was no significant relationship between use of OS and
participation of Japanese patients.
Potential factors of approvals based on surrogate end points
were identified as ‘orphan drug designation in Japan’ and ‘accelerated approval in FDA’. The reason for ‘orphan drug’ becoming a potential factor is probably attributable to the limitation in
the size of clinical trials as well as in trial design owing to the
rarity of the target disease, leading to inevitable situations where
there is no other choice but to use surrogate end points.
Furthermore, a report in the USA describes that, compared with
drugs for non-orphan diseases, a larger number of oncology
drugs have been granted an orphan drug designation by the
FDA on the basis of clinical studies that used response rate as an
end point instead of OS [9]. This result is consistent with our
findings. The accelerated approval program is a system of the
FDA that aims to promote the development of drugs for highly
serious indications, and using surrogate end points is common
under this program [10]. We considered that the correlation
between accelerated approval and surrogate end points was
Volume 26 | No. 1 | January 2015
Surrogate
endpoint
Survival
endpoint
%
61.3%
67.3%
68.3%
61.9%
69.0%
56.0%
80.0%
58.6%
94.1%
57.6%
66.7%
64.7%
30.8%
80.7%
60.0%
66.7%
64.0%
65.5%
69.7%
62.0%
55.3%
77.8%
83.3%
60.0%
57.9%
67.2%
58.7%
73.0%
82.6%
58.3%
100%
64.6%
67.5%
33.3%
90.9%
61.1%
Total
65.1% 29
54
N
12
17
13
16
18
11
5
24
1
28
5
24
18
11
8
21
9
20
10
19
21
8
3
26
8
21
19
10
4
25
0
29
25
4
1
28
%
38.7%
32.7%
31.7%
38.1%
31.0%
44.0%
20.0%
41.4%
5.9%
42.4%
33.3%
35.3%
69.2%
19.3%
40.0%
33.3%
36.0%
34.5%
30.3%
38.0%
44.7%
22.2%
16.7%
40.0%
42.1%
32.8%
41.3%
27.0%
17.4%
41.7%
0.0%
35.4%
32.5%
66.7%
9.1%
38.9%
N
31
52
41
42
58
25
25
58
17
66
15
68
26
57
20
63
25
58
33
50
47
36
18
65
19
64
46
37
23
60
1
82
77
6
11
72
%
37.3%
62.7%
49.4%
50.6%
69.9%
30.1%
30.1%
69.9%
20.5%
79.5%
18.1%
81.9%
31.3%
68.7%
24.1%
75.9%
30.1%
69.9%
39.8%
60.2%
56.6%
43.4%
21.7%
78.3%
22.9%
77.1%
55.4%
44.6%
27.7%
72.3%
1.2%
98.8%
92.8%
7.2%
13.3%
86.7%
34.9% 83 100%
Odds
ratio
95% CI
(confidence interval)
Fisher’s exact
Lower limit Higher limit
test P value
0.769
0.305
1.942
0.638
1.325
0.536
3.279
0.647
1.746
0.665
4.587
0.318
2.824
0.930
8.573
0.080
11.789
1.475
94.223
0.004
1.091
0.334
3.561
1.000
0.106
0.037
0.307
0.000
0.750
0.266
2.115
0.600
0.936
0.351
2.493
1.000
1.410
0.553
3.579
0.493
0.354
0.134
0.937
0.039
3.333
0.877
12.670
0.094
0.672
0.235
1.918
0.585
0.526
0.207
1.338
0.247
3.393
1.028
11.199
0.043
1.547
0.317
1.547
1.000
4.160
0.713
24.258
0.171
6.364
0.772
52.466
0.087
Favor of survival<-- --> Favor of surrogate
0.01
0.1
1
10
100
Odds ratio
Figure 1. Forest plot of the odds ratios (ORs) and 95% confidence intervals (CIs) of each potential factor that affect using surrogate end point or survival end point. To compare the distributions of categorical attributes between surrogate endpoints and survival endpoints supporting approval, Fisher’s exact test for a 2-by-2 contingency table was used. To compare potential factors that may have potential correlation with
using surrogate endpoints or survival endpoints, logistic regression models were adapted. From these models, the ORs and 95% CIs were estimated. The vertical lines indicate an OR of 1.0, values <1.0 favor survival
as an end point, and values >1.0 favor surrogate end points. Plus sign represents the OR of each potential factor. The horizontal line represents the 95% CI and indicates that the CI extends beyond the scale of
the plot.
original articles
doi:10.1093/annonc/mdu500 | 
N
iNDA
19
NDA
sNDA
35
Molecularly targeted
28
Mode of action
Other type
26
Non-major cancer
40
Type of cancer
Major cancer
14
Yes
20
Nomal NDA in Japan
No
34
Yes
16
Orphan designation in Japan
No
38
Public knowledge-based
Yes
10
application in Japan
No
44
Yes
8
Priority review in Japan
No
46
Special committee on
Yes
12
unapproved drug in Japan
No
42
Resistant or 2nd line<
16
Limitation of Indication
Nothing or 1st line
38
All case investigation
Yes
23
after approval
No
31
Bridging
26
Development style 1
Other style
28
Simultaneous, catch up 15
Development style 2
Other style
39
Fast track designation
Yes
11
in FDA
No
43
Priority review and/or
Yes
27
orphan designation in FDA
No
27
Accelerated approval
Yes
19
designatnion in FDA
No
35
Breakthrough therapy
Yes
1
designation in FDA
No
53
FDA approval when
Yes
52
Japan approval
No
2
Number of patients in
Less than 100
10
pivotal clinical study
Over 100
44
Total
Annals of Oncology
Volume 26 | No. 1 | January 2015
Potential factors
original articles
identified in our study because of the direct inclusion of clinical
trials that used surrogate end points under the accelerated approval designation of the FDA to the clinical data package for
the regulatory submission of approval in Japan.
The FDA held vigorous discussions on end points used in
clinical studies of oncology drugs after 2000 [11, 12], and
pivotal studies of drugs for cancer without alternate therapy
started using surrogate end points such as response rate, PFS,
and time to progression [13–19]. The programs of accelerated
approval allow consultations to be held with the FDA regarding
whether to use surrogate end points is feasible and also allow
such clinical studies to be conducted [20]. Japan has many expedited programs in regulatory systems including orphan drug
designation [21], priority review [22], public knowledge-based
application [23], and a special committee on unapproved drugs
[24]. However, the main purpose of these programs in Japan
was reduction in drug lags between Japan and the USA/EU and
catching up with the USA and EU [25]. Japan does not have an
accelerated approval program and has had no system for discussing surrogate end points so far. We consider that developing
a system for accepting surrogate end points in the Japanese
regulatory system is important to approve oncology drugs
quickly in Japan by itself.
acknowledgements
The authors wish to thank Tomoe Fujishima and Yoko Inaba
for supporting oncology drugs database making.
disclosure
HM is an employee of Astellas Pharma, Inc. TK has declared no
conflicts of interest.
references
1. Japan Antibiotics Research Association. Guideline for evaluation methods of
anticancer drugs in Japan. Mix, 1991. (in Japanese).
2. Ministry of Health, Labour and Welfare. The revision of the guideline for clinical
evaluation methods of anticancer drugs in Japan. 2005. http://home.att.ne.jp/red/
akihiro/anticancer/MHLW_gl_notice.pdf (in Japanese) (23 June 2014, date last
accessed).
3. Pazdur R. Endpoints for assessing drug activity in clinical trials. Oncologist 2008;
18(Suppl 2): 19–21.
4. Shea MB, Roberts SA, Walrath JC et al. Use of multiple endpoints and approval
paths depicts a decade of FDA oncology drug approvals. Clin Cancer Res 2013;
10: 3722–3731.
5. Ocana A, Tannock IF. When are ‘Positive’ clinical trials in oncology truly positive?
J Natl Cancer Inst 2011; 103: 16–20.
 | Maeda and Kurokawa
Annals of Oncology
6. Brown JS, Tadmor BB, Lasagna L. Availability of anticancer drugs in the United
States, Europe and Japan from 1960 through 1991. Clin Pharmacol Ther 1995;
58: 243–255.
7. Adams CP, Brantner VV. Spending on new drug development. Health Economics
2010; 19: 130–141.
8. Furuse K. Phase III study. Jpn J Cancer Chemother 1995; 22: 611–615
(in Japanese).
9. Kesselheim AS, Myers JA, Avorn J. Characteristics of clinical trials to support
approval of orphan vs nonorphan drugs for cancer. JAMA 2011; 305:
2320–2326.
10. Johnson JR, Ning YM, Farrell A et al. Accelerated approval of oncology products:
the food and drug administration experience. J Natl Cancer Inst 2011; 103:
636–644.
11. Johnson JR, Williams G, Pazdur R. End points and United States Food and Drug
Administration approval of oncology drugs. J Clin Oncol 2003; 21: 1404–1411.
12. Martell RE, Sermer D, Getz K et al. Oncology drug development and approval of
systemic anticancer therapy by the US food and drug administration. Oncologist
2013; 18: 104–111.
13. Hirschfeld S, Pazdur R. Oncology drug development: United States Food and Drug
Administration perspective. Crit Rev Oncol Hematol 2002; 42: 137–143.
14. Verma S, McLeod D, Batist G et al. In the end what matters most? A review of
clinical endpoints in advanced breast cancer. Oncologist 2011; 16: 25–35.
15. Giessen C, Laubender RP, Ankerst DP et al. Progression-free survival as a
surrogate endpoint for median overall survival in metastatic colorectal cancer:
literature-based analysis from 50 randomized first-line trials. Clin Cancer Res
2013; 19: 225–235.
16. Paoletti X, Oba K, Bang YJ et al. Progression-free survival as a surrogate for overall
survival in advanced/recurrent gastric cancer trials: a meta-analysis. J Natl Cancer
Inst 2013; 105: 1667–1670.
17. Halabi S, Rini B, Escudier B et al. Progression-free survival as a surrogate endpoint
of overall survival in patients with metastatic renal cell carcinoma. Cancer 2014; 1:
52–60.
18. Lee L, Wang L, Crump M. Identification of potential surrogate end points in
randomized clinical trials of aggressive and indolent non-Hodgkin’s lymphoma:
correlation of complete response, time-to-event and overall survival end point. Ann
Oncol 2011; 22: 1392–1403.
19. Buyse M. Use of meta-analysis for the validation of surrogate endpoints and
biomarkers in cancer trials. Cancer J 2009; 15: 421–425.
20. Lanthier ML. Accelerated approval and oncology drug development timelines.
J Clin Oncol 2010; 14: e226–e227.
21. Buckley BM. Clinical trials of orphan medicines. Lancet 2008; 371: 2051–2055.
22. Farrell AT, Papadouli I, Hori A et al. The advisory process for anticancer drug
regulation: a global perspective. Ann Oncol 2006; 17: 889–896.
23. Ito Y, Narimatsu H, Fukui T et al. Critical review of ‘Public domain
application’: a flexible drug approval system in Japan. Ann Oncol 2013;
24: 1297–1305.
24. Maeda H, Kurokawa T. Differences in maximum tolerated doses and approval
doses of molecularly targeted oncology drug between Japan and Western
countries. Invest New Drugs 2014; 32: 661–669.
25. Yonemori K, Hirakawa A, Ando M et al. The notorious ‘drug lag’ for oncology drugs
in Japan. Invest New Drugs 2011; 29: 706–712.
Volume 26 | No. 1 | January 2015