Antidepressant Drug
Development in Japan:
Current & Future Horizons
Doug Berger
Keywords: Japan, Drug development, Antidepressants, Bridging studies

Almost ten years has passed since it
was noted that the number of new
psychiatric drugs on the market in
Japan had significantly lagged behind Westerncountries.1 How has this changed over the lastten years, and what are the current challenges
for pharmaceutical companies trying to enter
this potentially lucrative market, especially forthe most widely-used class of psychotropics,
antidepressants?
Although large epidemiological studies
have not been done in Japan, It
is thought that up to 6 million
Japanese suffer from depression2
with a lifetime prevalence of
13-17%.3 This is similar to thatseen in Western countries: theDepression Research in European
Society (DEPRES) study foundthat almost 16% had sufferedfrom depression in their lifetime.4
A large proportion of depressed
patients are undiagnosed or evenuntreated in milder forms of the disease
and often have physical symptoms;5 75% of
these patients are thought to be seen in thegeneral medical clinics,6 where it is estimatedthat the primary reason for up to 6% of allpatients’ visits to the clinic is depression.7
Many psychiatrists promote themselves aspractitioners of ‘Psychosomatic Medicine’ or‘Neurologic Internal Medicine’, however, andthese clinics would then be classified as ‘InternalMedicine’ or ‘General Medical Clinics’ forstatistical purposes. The current antidepressantmarket size in Japan is equivalent to about
US$650 million, with sales of paroxetine(Seroxat/Paxil) making up approximately half of
this value.
Clinical trials and many clinicians in Japanuse the criteria published in “Diagnosticand Statistical Manual of Mental Disorders,
4th Edition”8 (DSM-IV) to categorise theirdiagnoses. However, many psychiatrists still use
traditional Japanese nomenclature of psychiatricillnesses, using terms like ‘Autonomic Nervous
32

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Dysfunction’, ‘Vague Somatic Complaints’,‘Psychologic Reaction’ to describe conditions
that are probably largely comprised ofdepressive and anxiety disorders as definedby DSM-IV. This is partly due to cultural habit,
partly due to lack of training in the use of DSMIV criteria, and partly due to hesitancy on thepart of the clinician to stigmatise the patientwith a diagnosis of depression. This disparityof diagnosis can lead to difficulties whencomparing cases with the international
literature, and could lead to treatment
options being missed.

Regulatory effect on
antidepressant trials inJapan

While the market has seen theentry of the SSRIs fluvoxamine(‘Luvox’ from Fujisawa, and‘Depromel’ from Meiji Seika),paroxetine (‘Paxil’ from GSK),and the SNRI milnacipran(‘Toledomin’ from Asahi
Kasei-Janssen), other blockbuster
antidepressants including sertraline (‘Zoloft’from Pfizer), fluoxetine (‘Prozac’ from Eli Lilly)
and others are either still in development or
have essentially been abandoned with respect tothe Japanese market.
Slowly, the Japanese regulatory system runby the Ministry of Health Labor and Welfare(MHLW) has required that the criteria forclinical development in Japan catch up with
the quality seen in the West. For example,
none of the antidepressants on the market in
Japan has been studied using placebo controls
in Japan, but this is now changing. Previous
clinical developments have pitted the newdrug against a drug already on the marketusing a ‘non-inferiority’ method of comparison.
In studies of antidepressants, this method isknown to be susceptible to ‘placebo effects’, ie,
depressive symptoms lifting due to effects otherthan pharmacologic drug effect. For example,
if patients know that that they are definitely
receiving an ‘active’ drug, having been told that

there is no placebo arm in the study, this could
be sufficient to cause a response. Additionally,some study subjects with relatively mild
depression might be likely to recover naturally
over time, whichever treatment they receive.
Traditionally, conducting clinical
trials in depression has been asensitive topic because of theperceived risk of suicide
in an untreated depressed
patient. However, someJapanese investigators
have been calling for anumber of years for useof placebo in carefully
selected depressed
patients. Recent surveys
have found that themajority of Japanese
psychiatrists think that, atleast in principal, it is both ethicaland scientifically valid to carefully
conduct clinical trials with placebo control
in depressed patients in Japan. This has beenbacked by a push from industry, presenting datafrom studies conducted in the West showingthat the suicide attempt rate is no different
in active vs. placebo arms. The Japanese
regulatory authorities have recently requested
that compounds starting clinical development
in Japan should have dose-finding studies
conducted against placebo.

virtually the entire class of ‘cerebral metabolicenhancers’ used for post-stroke syndromes andother cognitive disorders including depression
was eliminated from the marketplace because ofperceived lack of efficacy and high cost to thenational health system. Several post-marketing
trials were requested and the resultant lack ofpositive findings led to the decline of a market
worth hundreds of millions of dollars.

Bridging of global data intoJapan

Adoption of the ICH guidelines9 inJapan makes it possible in principal to‘bridge’ clinical trail data from outside
Japan into the Japanese data package
for NDA. However, whether this ispermitted in practice for a given drug
could be considered to depend moreon the potential importance of that
drug to medical care in Japan, than the)oftZolscientificlogic of the data to be bridged. For(ineralt
example,anovel
drug for influenza was able torSe‘bridge’ overseas data to meet a considerable
portion of the Japanese requirements and gain
entry into the Japanese market. Conversely,
antidepressant drugs used in millions of patientsover several years in multiple countries outside
Japan are still required to have pharmacokinetic,

Other compounds have already completed
clinical studies in Japan using a ‘pseudoplacebo’ (ie, very low doses of an activecomparator), or relapse prevention studies(in which some subjects who respond to theactive drug are then switched to placebo andcompared against those remaining on theactive drug). Companies developing these drugs
are now being told to conduct a formal doseresponse study with placebo control before
submitting a New Drug Application (NDA) for
sale in Japan. Naturally, this has delayed theentry of these antidepressants into the market
in Japan by many years and cost many more
millions of dollars in R&D expenditure.
The effect of the political climate on drug
development in Japan also cannot beunderestimated. The authorities running
the Japanese national medical insurance
system appear very careful to contain apotentially explosive market for such drugsas antidepressants, which could conceivably
be used for persons spanning a wide rangeof psychological distress. In the late 1990s,
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dose-finding, elderly, and long-term studies
conducted within Japan. In addition, a noninferiority trial comparing the developmental
drug with an antidepressant already on themarket in Japan is also required in order todetermine how the drug’s action should
be viewed vis a vis prior drugs on theJapanese market and in a Japanese
medical environment.

process of this drug in Japan. In addition, ifa direct comparison of Japanese to Westernpersons in a Phase I study finds similarity inpharmacokinetics, it might even be reasonable
then for Japanese study sites to contributesubjects to a global development programthat would also lead to a NDA in Japan,
just as centres across continents
now participate in multinational
clinical trials leading to NDAs in
the USA and Europe.

We would hope that, eventually,
antidepressants could beapproved in Japan withbridging studies. For example,
if a direct comparison between
Japanese and Western persons
in a Phase I study finds similar
pharmacokinetics, and if a dosefinding study in Japan shows
similar dosing and similar safety
and tolerability with global dose-finding
studies, then a NDA would seem valid, especiallyfor a drug that is already on the market
internationally. Further comparison with adrug already on the Japanese market in a noninferiority study where both groups show equal
likelihood to respond does not seem to add
substantial clinical information to the approval

Conclusion

The factors confronting
the clinical development of
antidepressants in Japan are also
common to other CNS medicinalsin Japan. Both scientific logicandpolitical mechanisms from)atrox
eSbothwithin
as well as from outsideil/Pax(eJapan might be able to nudge the approvaltin
oxe process towards accepting more bridging
Parstudies, as well as global studies done withcontributing Japanese sites for NDA in Japan.
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Volume 16Number 7 September 2005

development of CNS compounds in Japan inorder to avoid the pitfalls of delayed timelines
and even requirements to repeat studies. Asin many areas of doing business in Japan, one
needs to have access to Japanese experience,and the will to persevere and to dig deep into
one’s pocket before hoping to succeed in theland of the rising sun.
Doug Berger MD, PhD (www.japanpsychiatrist.com/
DrugDev.html) is Medical Director, Tokyo Meguro CounselingCenter, Tokyo, Visiting Assistant Professor of Psychiatry,
Albert Einstein College of Medicine, New York, and acts as aConsultant to the pharmaceutical industry in Japan.

References
123Berger D & Fukunishi I (1996): PsychiatricDrug Development in Japan, Science 273(July 19), 318-319.
Watanabe et al (1997): Primary caretreatment of depression Q&A (in Japanese),
Second revised edition. p1. Kanehara
Shuppansha.
Kasper, S (1997): Treatment of unipolar
major depression: algorithm forpharmacology. Int j Psychiat Clin Practice 1(suppl. 1) S5-S7.

4567
8
9Lepine J-P, Gastpar M, Mendlewicz J, Tylee
A (1997): Depression in the community:
the first pan-European study DEPRES(Depression Research in European Society).
Int Clin Psychopharmacol 12, 19–30.
Sarai, Keisuke (1997): Pharma Medica (InJapanese) 15(10), 41.
Watanabe, Yoichiro et al (1984): Nihon
Yakuji Hokoku [Japan Regulatory Report] (InJapanese) 3149, 48.
Tsuda, Tsukasa (1992): Igaku no Ayumi[Medical Progress] (In Japanese) 160 (10),819.
American Psychiatric Association (1994):
Diagnostic and Statistical Manual of Mental
Disorders, 4th Edition, ISBN: 0890420629
Juillet Y (2003): Internationalization ofregulatory requirements. Fundam Clin
Pharmacol. Feb; 17(1), 21-5.

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