LECTURE

Clinical Research in Japan: Past, Present and Future
Yuji Sato and Keisuke Koyama

Centre for Clinical Research, School of Medicine, Keio University
Tokyo, Japan(Received for publication on September 4, 2009)(Revised for publication on November 26, 2009)(Accepted for publication on March 18, 2010)

The volume of clinical research carried out in Japan is relatively small by global standards, especially when compared with the country’s contributions to basic research. Although the academic quality of the clinical research done here is generally high, its relative paucity has had anumber of alarming consequences, e.g., delays in the approval of important new drugs andmedical devices caused by difficulties in clinical trials, leading to the limited availability ofnovel treatments for Japanese patients. This article aims to present an overview of current
clinical research activities in Japan and to summarise the historical, socio-cultural and regulatory issues underlying the current situation. Suggestions are made as to how the present problems might be resolved and how a brighter future for clinical research might be achieved.
(Keio J Med 59 (3) : 104－109, September 2010)

Keywords: clinical research, drug lag, clinical trials, research infrastructure
Introduction

Japanese Clinical Research: The Present Situation

General longevity, comprehensive health insurance
coverage and the wide availability of cutting-edge medical equipment, all achieved under tightly controlled
healthcare budgets, point to the conclusion that Japan ishome to a high level of cost-effective medical scienceand practice. However, there is a significant disparity between the basic sciences and clinical sciences when it
comes to Japanese medical research output as measured
by the number of articles published in leading peer-reviewed international journals.1 This disparity between
basic and clinical research reflects the widespread difficulty in Japan of conducting the large-scale clinical trials
that form the subject matter of the majority of originalarticles published in first-class clinical journals. This article attempts first to summarise the present status ofclinical research in Japan, second to address the multifaceted issues associated with the country’s “clinical research lag”, and third to present several paths forward
and suggestions for improvement.

Rahman and Fukui 1 have examined via MEDLINE
different countries’ shares of basic and clinical research
articles published between 1991 and 2000 in 13 leading
journals, 6 of them basic science journals (Cell, Nature,
Nature Genetics, Nature Medicine, Neuron and Science),
and 7 clinical medicine journals (The American Journalof Medicine, Annals of Internal Medicine, Archives of Internal Medicine, BMJ, The Journal of the American
Medical Association, The Lancet and The New England
Journal of Medicine). Their results are shown in Table
1.
In terms of the share of published articles, Japanranked 4th in basic science and 14th in clinical research.
These results substantiate our contention that there is asignificant lag in clinical research as compared with basic research in Japan, although the limited number ofscientific journals researched in the study means thatsome caution is necessary in interpreting the results.
To further examine Japanese research output in relation to the relative productivity of individual research institutions, we carried out a literature search of PubMed.
Modern clinical research, in particular that based on

Reprint requests to: Yuji Sato, MD, Centre for Clinical Research, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582,
Japan, E-mail: yjsato@sc.itc.keio.ac.jp104Keio J Med 2010; 59 (3): 104－109

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Table 1 Shares of the 20 top-ranking countries for articles in basic and clinical medicine (from “A decline in the U.S. share ofresearch articles”, Rahman M, Fukui T: 2002; N Eng J Med; 347: 1211)
Shares (%) of the 20 Top-Ranking Countries
for Basic Science Articles

Shares (%) of the 20 Top-Ranking Countries
for Clinical Articles

Country

1991-2000(N=23,168)

Country

1991-2000(N=26,945)

United States

66.4

United States

53.7

United Kingdom

8.4

United Kingdom

18.3

Germany

4.8

Canada

2.8

Japan

3.3

Netherlands

1.6

France3.1

France1.4

Canada

2.7

Italy

1.2

Switzerland

1.9

Australia

1.1

Netherlands

1.1

Germany

0.9Australia

0.9

Israel0.8

Sweden0.8

Switzerland

0.8

Italy

0.8

Denmark

0.7

Israel0.8

Sweden0.7Austria

0.4

Finland

0.6

Belgium

0.4

Japan

0.6

Spain

0.3

Spain

0.5

Finland

0.3

New Zealand

0.5

Denmark

0.2

Ireland

0.4

China

0.1

Belgium

0.3

Norway0.1

Norway0.3

New Zealand

0.1South Africa

0.3

multicentred clinical trials, invariably involves a large
number of investigational sites, so we used the affiliationof the first author of each article as the index researchorganisation representing the publication. Figure 1
shows the 20 most productive research organisations according to the number of articles (in both basic and clinical medicine) published in English by their researchersand cited in PubMed between 1998 and 2007.
Amongst the top 20 institutions listed, Kyoto University, Tokyo University, Osaka University and Keio University ranked as the 7th, 8th, 9th and 13th most productive,
respectively. However, when only the articles publishedin the 4 leading clinical journals (The New England
Journal of Medicine, The Lancet, The Journal of theAmerican Medical Association and BMJ) are counted,
the productivity of these 4 universities drops significantly, as shown in Figure 2, whilst the top 5 institutions
worldwide (Harvard, Johns Hopkins, Yale, Imperial College London and Stanford) far outrank the others. Notably, Keio University ranks 23rd in clinical research activities in this list (and therefore is not listed in Figure 2),
and is superseded by other Asian universities.
These analyses suggest first that Japanese medical re-searchers tend to gravitate towards basic research, andsecond that only a relatively small percentage of articles
by Japanese researchers are published in the four leading
clinical journals, which tend to favour articles describing
large-scale prospective trials. In other words, there are
two sorts of “lag” present in Japanese medical research:first, the lag between basic and clinical research, andsecond, the lag between articles based on case reports/case series and those based on large-scale trials (the former constitute most of the Japanese clinical articles published in the leading international journals).
Factors Related to the Present“Clinical Research Lag” in Japan
Historical background
In order to import Western science and technology rapidly, it was customary in 19th century Japan to identify
the leading Western country in each target specialty as
the main source of knowledge. In many branches of thenatural sciences, German-speaking countries were designated as the national role models, as exemplified by the106

Sato Y and Koyama K: Clinical Research in Japan

Fig. 1 Number of articles (registered in PubMed, 1998-2007) in both basic and clinical research by the most productive 20
institutions.

appointment of two German physicians as the de facto
founding professors of internal medicine and surgery at
the Western-style medical schools in Japan. This may
have helped foster in Japanese medical schools an intellectual milieu where German-style rigorous and systematic basic research was more valued than clinical research. However, von Bältz, one of the aforementioned
German physicians, records his observation2 that Japanese medical students had a propensity to focus more on
basic research activities than clinical training, since theformer, they believed, would be more advantageous totheir career than the latter. It may be reasonable, then, tostate that the current Japanese academic orientation towards basic research is a legacy of the intellectual fervour of past generations of Japanese doctors to pursue
quick, tangible achievements in their laboratories. One
cannot help but be reminded of the resemblance between
this 19th-century Japanese phenomenon and the publishor-perish Zeitgeist that would overwhelm academia
globally one century later.
The Second World War and its accompanying socioeconomic upheavals shifted the hub of science from
Western Europe to the United States. Accordingly, Japanswitched its primary source of medical knowledge from
Germany to the US. However, the basic academic structure in Japan, e.g. the medical education system, underwent few changes. Therefore, at a time when investments to enable large-scale clinical research were being
made in the US and elsewhere, no equivalent initiatives
were given the priority they deserved in Japan.
The notion of the clinical trial as a valid and reliable
method of confirming the effectiveness of novel treatments came into being in the UK in 1948. 3 The firstequivalent randomized controlled trial (RCT) in Japanwas carried out in 1957. Sunahara argued that the resultsof these early Japanese RCTs received little international
attention, because they involved a number of drugs not
approved or used outside Japan.4 This tendency for Japanese clinical research to be underrepresented overseas,rightly or wrongly, can still be seen today.5 This may not
be because Japanese trials are undervalued elsewhere,
but simply because the procedures surrounding the development, evaluation and approval of drugs have differed from those in the rest of the world for such a longtime.
In addition to the longstanding Japanese academic predilection for basic research, some industry-sponsoredclinical trials of novel drugs have not necessarily met
global standards, giving Japanese physicians the impression that clinical research is somewhat less scientificallysound and valuable than basic research. Protectionist
governmental policies favouring pharmaceuticals of Japanese origin, along with archaic business practices,6 may
also have helped hold Japanese researchers back fromcatching up with the flourishing clinical research outside
the country.
The advent of ICH-GCP (The International Conference on Harmonisation of Technical Requirements for
Registration of Pharmaceuticals for Human Use - Good
Clinical Practice) in Japan in 1997 occasioned belated
awareness that Japanese clinical research lags behind interms of output, quality and infrastructure.
Today, the development of innovative treatments by
way of global trials is an efficient way both to minimize
the burden of development and to enable quicker regulatory approval of, and therefore access to, novel treat-Keio J Med 2010; 59 (3): 104－109

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Fig. 2 Number of articles featuring human clinical studies appearing in the four leading clinical journals (N Eng J Med, Lancet,
JAMA and BMJ) in the period 1998-2007 by the most productive 20 institutions.

ments. However, the globalization of clinical trials canpose problems7 despite some countervailing proposals.8
Although concerted efforts are required in Japan to improve the infrastructure for clinical research, these efforts must be buttressed by high ethical and scientificstandards. It is, after all, only natural that the interests ofinvestigators in furthering their careers and the interestsof sponsors in seeing trials completed quickly may conflict with ethical considerations and the proper protection of the trial subjects.
Infrastructure for clinical research: hitherto underestimated aspects
It is an outdated stereotype to picture a researcher inbasic science as a solitary figure working alone in hislaboratory, since in reality almost no basic research isfeasible without collaboration amongst many scientists
with different subspecialties. Likewise, it is equallywrong to believe that clinical research, in particularlong-term, multi-centred clinical trials, can be conductedby a handful of clinicians. As the recently coined term“clinical trialist” (according to the Oxford English Dictionary,9 its first usage as “One who takes part in clinicaltests or trials of new drugs” is attributed to a 1997 article
in The Lancet1 0) implies, current standards require diverse expertise that can only be provided by a myriad ofexperts from different specialties. These experts usually
include investigators well versed in the disease or therapeutic area in question, research nurses or clinical research coordinators proficient in the operational aspectsof trials and related regulations, administrators to deal
with the research contracts and financial aspects, biostatisticians and data managers. The availability of these
professionals at investigational sites constitutes an important part of the operational infrastructure essential to
the smooth, efficient and accurate conduct of clinical trials. This infrastructure is regrettably not in place in Japan, first because the teaching hospitals are generally
understaffed, underfinanced and preoccupied with routine health care provision, and second because the aforementioned basic research orientation in Japan means thatlittle attention has been paid to the operational aspects ofresearch. This unfavourable situation has now beenrecognised, and a number of initiatives for improvement
are under way, a prime example being the Ministry of
Health, Labour and Welfare’s 5-year plan to boost clinical trials.
However, several years before these initiatives were
put in place in Japan, the Republic of Korea had alreadystarted investing huge amounts of money and energy inestablishing clinical research centres, an initiative next
to which Japan’s efforts pale by comparison.11 The last
several years have seen a dramatic increase in the number of multinational clinical trials carried out in Korea:
148 in 2007, as compared with the 32 conducted in Japan in the same year.
In Japan, against this unfavourable background, various contract research organisations (CROs) have been
established in the private sector to assume supplementary roles in research operations. In response to ever-increasing developmental costs and demands to conduct

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studies efficiently,11 the pharmaceutical industry has
been outsourcing more developmental functions, e.g.
field monitoring and data management, to these CROs.1 2
It might seem sensible for academic institutions also tooutsource such functions to CROs if all the required
functions cannot be set up in-house. However, severely
capped healthcare and academic budgets could not possibly cover the costs of outsourcing of this type at the
moment, since the pricing structures for these CROs aretargeted at industry, making them far beyond the range
acceptable to academia.
One critical factor that makes clinical research infrastructure difficult to set up is, as mentioned earlier, thegeneral shortage of medical staff in Japanese academia.
According to the OECD’s health data 2009, 1 3 Japanranks 27 th in the number of practicing physicians per1000 population. Poor differentiation between primary,secondary and tertiary/specialist medical care in Japan
has resulted in an atrocious workload for physicians,
thereby further restricting their capacity as investigators.
The poorly differentiated patient populations at majorteaching hospitals can also restrict these institutions’ability to function as effective investigational sites, as
they have to accept patients outside the therapeutic areas
they specialise in. This negatively affects the number ofpatients that can be enrolled per site, adding to the already limited enrolment efficiency in Japan.
Last but not least, a fundamental problem affecting
clinical research is funding. With the ever-increasing scientific complexity and regulatory requirements associated with clinical research, costs have been rising steadily.
One driving factor behind the USA’s outstanding clinicalresearch has been the enormous financial support provided largely by the federal government and industry.
But this support is now dwindling, which is causing apprehension about the future of academic research in theUSA. 1 4 The problem is all the more serious in Japan,
where research funding has always been notoriously paltry.
Socio-cultural factors hindering global trials in Japan
Several socio-cultural factors have served to hinder thecreation of an environment in Japan conducive to the
conduct of clinical research meeting global standards.
First, protectionist policies applied to the pharmaceutical industry have until recently demanded almost all therequired clinical, and even non-clinical, data pertaining
to drug approval applications to be of Japanese origin,
thereby rendering multinational trials difficult for Japanto participate in. Alleged ethnic differences between the“homogeneous” Japanese population and other ethnic
groups, including the Chinese and Koreans, are still often emphasised, even at a time when the concept of ethnicity itself has met trenchant criticism for its politicallyinflammatory nature1 5 as well as for its scientifically un-

Sato Y and Koyama K: Clinical Research in Japan

tenable premises. This excessive sense of Japaneseuniqueness in various areas –pharmacokinetic, sociocultural, ethnographic, etc.– has almost certainly delayed
Japanese participation in global trials.
Second, many Japanese patients seem to be unawarethat by taking part in clinical trials they not only makean important contribution to the advancement of medicine but also gain the opportunity to benefit personallyfrom novel treatment. Rather, they are likely to see a request to participate in a trial as coercion into being partof a hazardous experiment. Such negative and ill-informed images probably reflect both insufficient medical
literacy and a lack of any sense of altruistic moral civil
duty on the part of many Japanese patients.
Future Prospects
Most of the problems discussed above are interwoven
with the historical, socio-cultural and regulatory complexities of the country, and are thus not likely to bequickly resolved by implementing a new remedial policyor two.
Nevertheless, improvement of the research infrastructure is a sine qua non for the production of clinical research of a high standard, which is in turn essential if theoften outstanding basic and clinical innovations produced in Japan are to be recognised and accepted globally, and if novel therapeutic agents are to be quickly approved for use. Furthermore, since emerging Asian countries often have research infrastructures conducive to
multinational trials, industry may have even less incentive to sponsor trials in Japan; hence the fear that clinicalresearch in Japan is being “hollowed out”. It is extremely important that these problems be tackled urgently andthat the existing gaps and lags be filled.
Five practical measures to deal with these issues aresuggested:
1) Establishing a proper clinical research infrastructure2) Providing investigators with higher education inclinical research methodologies
3) Securing sufficient time for investigators to takepart in research activities as well as carrying out
their clinical duties4) Improving patients’ awareness and understanding ofclinical trials to boost their willingness to participate
5) Ensuring transparent and equal collaboration between academia, industry and regulatory agencies
It is to be hoped that these measures will be implemented over the next several years so that the clinical research lag can be rectified. However, given the plethora
of far graver issues that the beleaguered Japanese healthcare system faces, one can only wonder how greater investment in clinical research can be funded.

Keio J Med 2010; 59 (3): 104－109

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Conclusion

References

RCTs are touted as one of the best weapons in the clinical research armamentaria, but they have a number offlaws and limitations.1 6 At the very least, RCT results
need to be juxtaposed with, and preferably counterbalanced by, those obtained through other forms of research
to produce generally acceptable evidence upon which asound clinical judgment can be made. It is regrettablethat RCTs are not infrequently overvalued, regardless of
their range of applicability, a situation that has perhaps
been brought about by the belated awareness amongst
Japanese physicians of RCTs as providers of highly
ranked evidence. As a consequence, qualitative, casebased clinical studies have attracted less attention thanthey deserve. As Rawlins1 5 points out, experimentation,observation and mathematics all have crucial roles toplay in obtaining clinical evidence. Interventional quantitative research, as epitomised by RCTs, represents only
two of these elements, i.e., experimentation and extensively applied biostatistics. Frontline clinical researchseems no longer to rely solely on RCTs but attempts tofind ways of combining all three elements to obtain ahigher level of evidence. If Japan’s “clinical researchlag” is to be overcome, mastery of RCTs must be accompanied by a widened perspective that encompasses
evolving research methodologies. Whether this can beachieved will depend heavily on whether local issues
such as the shortage of medical manpower, differentiation between specialist and primary care, healthcare budget restrictions and domestic regulatory complexities areresolved in due time.

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