Psychiatric Drug Development in Japan -- Berger and Fukunishi 273 (5273): 318... 1/6 ページ

Current Issue

Previous Issues

Science ExpressMy ScienceScience Products

About the JournalHome > Science Magazine > 19 July 1996 > Berger et al. , pp. 318 - 319
Science 19 July 1996:
Vol. 273. no. 5273, pp. 318 - 319
DOI: 10.1126/science.273.5273.318

ADVERTISEMENTPOLICY FORUM

Psychiatric Drug Development in Japan
Douglas Berger and Isao Fukunishi
D. Berger is at the Tokyo Institute of Psychiatry, 2-18, Kamikitazawa, Setagayaku, Tokyo 156, Japan, and at theAlbert Einstein College of Medicine, Bronx, NY 10461, USA.
I. Fukunishi is at the Tokyo Institute of Psychiatry, 2-18, Kamikitazawa, Setagayaku, Tokyo 156, Japan.

ADVERTISEMENT

While psychiatrists in the West are reaping the benefits of thesurge in drug development during the past 10 years, psychiatrists
in Japan are currently treating mental illness with a
psychopharmacologic armamentarium that was considered stateof the art in the United States in the early 1980s. None of thenew generation antidepressants, antianxiety agents, orantipsychotics that have made great changes in the way
psychiatry is practiced in the West have yet been approved by
the Japanese Ministry of Health and Welfare (MHW).
Considering Japan's cutting edge position in most other areas oftechnology, this lag seems a bit surprising.
A closer look at the Japanese drug approval system and its
relation to mental health makes some of the reasons for this lag
clearer. First, even if a drug has been approved in the West,
there is an incredible cost to the pharmaceutical industry incarrying out the clinical drug trials that need to be repeated inJapan. This financial investment may prove too burdensome fora drug company, especially if the market for the product seems
sparse. Additionally, because of inherent difficulties in the way
drug trials are carried out in Japan, the methodology often has
flaws, and subtle psychopharmacologic drug effects may not beseen.

http://www.sciencemag.org/cgi/content/full/273/5273/318?ijkey=ulgp674JjYq/... 2008/07/19

Psychiatric Drug Development in Japan -- Berger and Fukunishi 273 (5273): 318... 2/6 ページ

Prozac (fluoxetine, produced by Eli Lilly), which began todominate the antidepressant market in the United States in thelate 1980s, is not being developed in Japan. It is ourunderstanding that this is because of the high cost of redoing theclinical drug trials and the perceived lack of an adequate market.
Depressed individuals in Japan often do not visit their family
physician, and if they do they are often told that they just need torelax more. The other selective serotonin reuptake inhibitors
besides Prozac, including Zoloft (sertraline, Pfizer), Paxil(paroxetine, SmithKline Beecham), and Luvox (fluvoxamine,Solvay), have had ongoing drug trials in Japan since the early
1990s, although approval applications for these drugs have notyet been submitted to the MHW.
Flaws in drug trial methodology seem to have resulted in theinability of Buspar (buspirone, Bristol-Myers Squibb) to beapproved. Buspar, a non-benzodiazepine anxiolytic that has
been shown to be effective and has been available in a numberof countries since the 1980s, was determined to be no more
effective than placebo by two multicenter double-blind trials inJapan (1). However, close scrutiny of these studies shows that
too few patients at too many centers led to intersite variation; inaddition, although more severely anxious patients would beexpected to respond, mildly anxious patients were included in a
protocol that was not long enough to detect improvement in a
medication with subtle anxiolytic effects (2). Similar protocol
designs in Japan were not even sensitive enough to findbenzodiazepines (that is, Valium) superior to placebo for anxiety
in five of six multicenter placebo-controlled studies, even thoughstudies performed outside Japan have concluded
overwhelmingly that anxiolytics are more effective than placebo(2). Although psychotherapy is thought to be more pertinent forpatients with low levels of anxiety, most Japanese psychiatrists
do not think that buspirone has any utility and usually prescribe abenzodiazepine for patients with all degrees of anxiety.

To Advertise
Find
Products

One important antipsychotic drug introduced in the early 1990s in
the West is Clozaril (clozapine, Sandoz). Although clozapine isADVERTISEMENT
virtually free from extrapyramidal motor side effects and has
FEATURED JOBS
been shown to have enhanced efficacy in 30 to 40% of otherwise
treatment-resistant schizophrenics (3), it is not yet approved inJapan and has not gained the favor of Japanese psychiatrists.
Although a clinical trial is ongoing, a trial of clozapine in Japan in
1974 in which the mortality rate due to agranulocytosis was felt to
be too high has left many Japanese psychiatrists with anunderstandable hesitancy toward its approval. There is also
concern that frequent testing for lowered white blood cellcounts a known but uncommon side effect makes patient
quality of life unacceptable. Sandoz has minimized the risk ofagranulocytosis in the United States by requiring that patientsregister in a nationwide blood testing data bank before they canreceive the drug. In addition, prospective patients must havealready failed a trial of two standard antipsychotics. The risk ofagranulocytosis is greatest during the first 3 months of treatment;

http://www.sciencemag.org/cgi/content/full/273/5273/318?ijkey=ulgp674JjYq/... 2008/07/19

Psychiatric Drug Development in Japan -- Berger and Fukunishi 273 (5273): 318... 3/6 ページ

the cumulative incidence is 0.8% after 1 year and 0.91% after
1.5 years (4). Clozapine is now widely used in the United Statesand other countries and is thought to be responsible for reduced
symptom severity and decreased hospital stays. Japanesepatients with chronic schizophrenia usually receive more than
one antipsychotic at the same time, and many of them spend
many years or their whole lives in for-profit private psychiatrichospitals.

AQUATIC BIOGEOCHEMIST
University of Montana
Montana
Institute for Diabetes,
Obesity andMetabolism/Department ofRadiology
University of Pennsylvania
Pennsylvania
Appointment of ExecutiveOther novel psychiatric medications have been approved in theUnited States but not yet in Japan. These include theantidepressants Wellbutrin (bupropion, Glaxo Wellcome; U.S.
approval in 1989, not in development in Japan), Effexor(venlafaxine, Wyeth-Ayerst; U.S. approval in 1994, currently indevelopment in Japan), and Serzone (nefazodone, Bristol-MyersSquibb; U.S. approval in early 1995, currently in development inJapan), as well as the antipsychotic Risperdal (risperidone,Janssen; U.S. approval in 1994, with plans to enter the Japanesemarket in mid-1996) and a drug for alcohol dependency, REVIA(naltrexone, DuPont Pharma; U.S. approval in 1995, not indevelopment in Japan).
Yutaka Mizushima, a past member of the MHW's New Drug
Committee and currently an Upper House Parliament Councilor
and member of the Committee on Health and Welfare, is trying toinitiate changes in the system. He has noted that there are too
many investigators at too many sites with too few cases at eachsite, and many of the investigators do not have sufficientknowledge or experience to perform drug trials (5). The DrugApproval Committee of the MHW has traditionally been
composed of university professors, who serve on the committee
in their spare time. Often, outcome end points have been
unclear, and it is the doctors' subjective feelings about
effectiveness rather than objective measures that havedetermined the outcome of trials. This process can lead to claims
that ineffective drugs are effective, and vice versa (6).

Director
National University ofSingapore
SingaporeDirector
University of Wyoming
Laramie, WY
POSTDOCTORAL POSITION
University of Pittsburgh
Cancer Institute
Pittsburgh, PA
Research Specialist
Johns Hopkins University
School of MedicineBaltimore, MD
Research Associate
Manchester Metropolitan
UniversityManchester, UnitedKingdomMore jobs

Clinical drug trials cannot ascertain the degree of improvement inobjective outcome measures (for example, quality of life,longevity) unless they are of adequate length and have adequate
follow-up. This is not yet the case in Japan. After a drug has
passed clinical trials, the MHW tends to approve the drug for awide range of related conditions without assessing efficacy (7).
Some foreign pharmaceutical executives have commented that it
is often difficult to get the chief investigators (usually academicphysicians) to exclude protocol violations or to discuss
methodology with them. The general consensus is that theprimary investigators have their own ways of doing things and do
not like to hear what the drug companies have to say.
On top of these difficulties, the combination of the antiviral
Sorivudine and the anti-cancer drug 5-fluorouracil was
associated with 15 deaths in 1993; as a result, both the MHW
and the drug companies have become especially sensitive toadverse effects, and the drug approval process has becomehttp://www.sciencemag.org/cgi/content/full/273/5273/318?ijkey=ulgp674JjYq/... 2008/07/19

Psychiatric Drug Development in Japan -- Berger and Fukunishi 273 (5273): 318... 4/6 ページ

even slower. Although the MHW charged Nippon Shoji, themanufacturer of Sorivudine, with failure to report two of threedeaths that occurred during phase III of the clinical trials andfailure to provide adequate package warnings on this side effect,
poor and hurried data review by an inadequately staffed drug
approval committee at the MHW is thought to be the actual
cause of the tragedy (7). In response, the MHW recently
proposed a plan to take effect in 2 years that includes hiring athird-party medicinal review organization to monitor the clinicaldrug trials, increasing drug trial site inspections, and more closely
reviewing informed consent procedures (8). There are also plansto greatly increase the size of the MHW staff; at present,considerably fewer personnel are involved in each new drug
application than in Western countries, and many are notscientifically qualified (9).
At the end of 1995, at the Third International Conference onHarmonization of Technical Requirements for Registration of
Pharmaceuticals for Human Use (in Yokohama), the international
community attempted to make the results of drug trials reciprocal
between nations. This action placed additional pressure on
Japan to improve its system. Reciprocity would greatly reducethe cost of drug development and would make the introduction ofdrugs to the Japanese market much more palatable for theinternational pharmaceutical companies. The establishment of aninternational organization that would review the clinical drug trialsof a compound and make recommendations for expeditedapproval in other countries that agree to this protocol is one way
to alleviate the need for repetitive studies. If such an organization
were funded by the various drug approval agencies of therespective countries, the burdensome reevaluation costs incurredby each country could be considerably reduced. [This kind ofprocess would need to take into consideration any ethnic
differences in drug metabolism; for example, Asians seem tohave lower hepatic metabolic capacities than do Caucasians,
and this difference may lead to differences in dosage (10).]The impetus for the MHW to improve its system has also comefrom sources other than the Sorivudine incident. Recently, theMHW reported that one of its departments did not adequately
assess blood products used to treat hemophilia for the absenceof the human immunodeficiency virus (HIV) in the mid-1980s,
even though the U.S. Food and Drug Administration had issued arecall order for these products (11). Limitation of their import wasdelayed by many months, and it is now estimated that about 40%of Japanese hemophiliacs have acquired HIV from bloodproducts (11).
Both the Sorivudine and blood product incidents have slowed
drug approval in Japan by making the MHW more cautious.
Methodology flaws inherent in the Japanese drug trial system will
be difficult to eradicate, however, because of the strong line ofauthority from the primary investigator down to thepharmaceutical drug trial coordinator, which creates animpediment to educating the investigator about proper drug trial

http://www.sciencemag.org/cgi/content/full/273/5273/318?ijkey=ulgp674JjYq/... 2008/07/19

Psychiatric Drug Development in Japan -- Berger and Fukunishi 273 (5273): 318... 5/6 ページ

methodology. In addition, because different investigators atdifferent sites each have their own way of carrying out a study,
the standardization of outcome measures for psychiatricdisorders will be difficult as well. If Japan can agree on accepting
more data from studies previously done in other countries, thedrug approval process could proceed much more quickly, andmore drug companies would submit approval applications if theircosts dropped. Efforts to educate primary physicians and thegeneral population about psychiatric illness would help tobroaden the market for these treatments by decreasing stigma
and increasing awareness about the large biologic component ofmany of these disorders and their cost to society.

REFERENCES
1.
2.
3.
4.
5.
6.
7.
8.

9.
10.
11.

F. Okada, Ann. Pharmacother. 29, 432 (1995) .
, Hum. Psychopharmacol. 8, 371 (1993).
D. Pickar, J. K. Hsiao, J. Am. Med. Assoc. 274, 981 (1995) .
J. M. J. Alvir et al., N. Engl. J. Med. 329, 162 (1993) .
Y. Mizushima, Nihon Enshou Gakkai Zasshi 15 (no. 2),93 (1995); ibid. (no. 3), p. 193.
K. Hayashi, Medical Asahi 24 (no. 2), 43 (1995).
"Blaming somebody else," Nature 371, 89 (1994).
"Rinshoushiken kara zenkeikaku chousa" (Investigating theentire drug trial process), Asahi Shinbun (Tokyo),
7 November 1995, p. 2.
M. Fukushima, Nature 342, 850 (1989) .
K. M. Lin, R. E. Poland, J. K. Lau, R.T. Rubin, J. Clin.
Psychopharmacol. 8 (no. 3), 195 (1988).
"Eizu chuukan houkoku: shinsou kaimei ni hodotouku'kentoushita' 'kentoushinai' " (AIDS interim report: It's still along way from clarifying the facts; did they check or didn'tthey?), Asahi Shinbun (Tokyo), 29 February 1996, p. 39.

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Psychopharmacology in a Globalizing World: The Use of
Antidepressants in Japan.
L. J. Kirmayer (2002)
Transcultural Psychiatry 39, 295-322
Abstract » PDF »Science. ISSN 0036-8075 (print), 1095-9203 (online)
Magazine | News | Signaling | Careers | Multimedia | Collections | Help | Site Map | RSS

http://www.sciencemag.org/cgi/content/full/273/5273/318?ijkey=ulgp674JjYq/... 2008/07/19

Psychiatric Drug Development in Japan -- Berger and Fukunishi 273 (5273): 318... 6/6 ページ

Subscribe | Feedback | Privacy / Legal | About Us | Advertise With Us | Contact Us© 1996 American Association for the Advancement of Science. All Rights Reserved.
AAAS is a partner of HINARI, AGORA, PatientInform, CrossRef, and COUNTER.

http://www.sciencemag.org/cgi/content/full/273/5273/318?ijkey=ulgp674JjYq/... 2008/07/19