Post on 21-Apr-2015
Clinical Trials in Korea: Why Korea?
Young Jack Lee, Ph.D.
President
LSK Global Pharma Services
Seoul, Korea
jacklee@lskglobal.com
Korea is new to modern day clinical trials. Before the IND (Investigational New Drug)
system was introduced in 2002, the Korea Food and Drug Administration (KFDA)
required safety and efficacy data of the investigational product for approving the clinical
trial application. This requirement effectively shut down trials of investigational new
products before 2002. Drug trials then were generally small with 30-90 patients.
Multinational sponsors had no IND approvals between 1993 and 2000 (see Figure 1).
(An IND trial before 2002 in Korea is a misnomer. It was a sort of bridging trial, not an
IND trial. But for convenience, I will keep abusing the term, IND.) KFDA, which was
established in 1998, approved five INDs for multinational sponsors in 2000. The
number jumped to 17 in 2002. KFDA approved 148 INDs for multinational sponsors in
2007. The number will be close to 250 this year, a fifty fold increase from year 2000
(see Figure 2).
The number of IND trials in Korea is now larger than in Japan. In 1993, there were
160 IND approvals in Japan and 18 in Korea. Since then the number of clinical trials
has been steadily increasing in Korea, while decreasing in Japan. In 2002, there were
55 IND approvals in Korea and 60 in Japan. In 2005, there were 185 IND approvals in
Korea while 96 in Japan (see Figure 1.), a complete reversal in a short period.
China is important for global drug development. According to the statistics presented
in April 2008 at the East Asian Pharmaceutical Regulatory Symposium 2008 in Tokyo,
Japan, however, the number of IND approvals for multinational sponsors in Korea is
larger than in China: 95 in 2005, 108 in 2006, and 148 in 2007 in Korea while 31 in
2005, 61 in 2006, and 53 in 2007 in China (see Figure 2 and 3). Although China is
expected to catch-up, at least for now Korea is more active in multinational trials than
China.
Multinational sponsors hold more Korean INDs than domestic sponsors since 2005.
This trend will continue and the gap will grow even further. For the Japanese drug
industry will increase clinical trials in Korea as the Japanese authority has started
accepting Korean clinical trial data for Japanese registration. Furthermore the
Japanese government is committed to regional clinical trials involving Japan, China and
Korea.
What attracts clinical trials to Korea? Look at Canada, Australia, and Singapore.
Although not known for pharmaceutical industry, these countries are hugely successful
in attracting global trials. All three countries have top class medical infrastructure,
well trained investigators, economic stability, high literacy rate, trial friendly regulatory
system, and English-speaking on top of those factors. In Asia, Hong Kong, Taiwan,
Malaysia and Korea come close to those three countries. Cost, although important,
may not be a crucial factor.
Korea may be best positioned among those four countries plus Singapore. Korea has a
large population (49 millions, larger than Singapore, Hong Kong, Malaysia, or Taiwan),
is economically strong (20,000 US dollars per capita income), and has advanced and
westernized medical infrastructure (better medical system than most East Asian
countries). Japan should be the country with better conditions for clinical trials than
Korea in East Asia if measured only those three factors. But Japan is known to be
overly conservative toward clinical trials and drug approvals, domestic or global.
Korea should stand out in East Asia.
I will review selected factors important for clinical trials.
Medical infrastructure
KFDA qualifies clinical trial sites. One hundred and twentyfour sites are now eligible
for clinical trials. Those sites are all teaching hospitals, large and self-contained with
modern medical equipment and laboratories. Most clinical trial hospitals have more
than 1,000 beds. The largest hospital has over 2,600 beds. These hospitals can run
clinical trials themselves, and they do not need SMOs (site management organizations).
Korean clinical trial sites may be best equipped in Asia, if not in the world. Teaching
hospitals have a down-side, however. Patients with common conditions such as light
injury, infection or pregnancy go to private hospitals or clinics, and trials for such
conditions are not easy in Korea. KFDA has recently relaxed its requirement that only
teaching hospitals can qualify as clinical trial sites. Now specialty hospitals and
general hospitals can participate in clinical trials if qualified by KFDA. Such hospitals
may need SMOs’ help. Furthermore some incentives may have to be offered for their
participation in clinical trials.
Investigator quality
Most investigators are trained in the US for 2-4 years after medical training in Korea,
and have academic appointment. They are exposed to US medical practices and
clinical trials. In addition, they command good English. Investigators even with no US
experience are familiar with clinical trials and US medical practices, probably a peer
influence. Korean investigators are actively engaged in medical research, rarely leave
the academic position until retirement, and are motivated to participate in global clinical
trials. When I contact investigators for feasibility of multinational clinical trials, I find
them generally enthusiastic. They are all familiar with clinical trial procedures and
well versed with GCP (Good Clinical Practice). Because Korean investigators are on
academic payroll, monetary reward is not a motivation.
Institutional Review Board (IRB)
Although central IRBs are in the book, I am not aware of any active central IRBs yet.
There is no commercial IRB either. Each teaching hospital has its own requirements
for clinical trials, reviews and approves clinical trials by itself. This causes some
minor nuisances. Different IRBs may request different protocol amendments. IRB
application procedures also vary from site to site. IRBs are responsible for approving
clinical trial agreement between the hospital and sponsor. But IRBs are generally
cooperative, and their actions rarely delay the study initiation.
Patient recruitment
Patients are recruited from investigator’s own pool of patients rather than referral.
Advertisement is placed often for clinical trials of disorders generally not seen in
teaching hospitals but rarely for serious disorders and diseases. The patient
recruitment practice may be the most important difference between West and Korea.
Korean investigators generally meet the recruitment timeline. I have seen trials in
which Korean sites started last but completed the recruitment first.
Compliance
It is well known that the higher the education level the better the compliance. Korea
has a high literacy rate (98 percent) and a high college education rate (84%). Our data
base shows a high compliance rate (mean of 91% with 70%-100% from 16 studies) and
a low drop-out rate (mean of 11% with 0-30% from 21 studies). These data are from
phase II, III, IV, and health food studies for which my company performed the data
analysis recently (see Table 1). We do not have Korean data from pivotal global
studies. The compliance rate of those studies may be better.
Cost-effectiveness rather than cost
If multinational sponsors expect low cost trials in Korea, then they will be disappointed.
A few potential overseas sponsors decided not to include Korean sites, because the
price was “too” high. Global clinical trials in Korea may cost about 50-70 percent of
the US cost, not cheap. Korea is a small densely populated country. Forty percent of
its population lives in and around Seoul, the capital city. Entire Korea can be covered
in one day. CRAs go to any part of Korea, complete monitoring, and return home in
one day. Most major hospitals are in the capital region, and are reachable in one hour.
Patients come to hospitals in Seoul from remote areas, and return home in one day.
CRAs are all centrally located, and can be supervised more readily. This geographical
proximity and the size of trial sites make the Korean clinical trial cost-effective.
Regulatory system
Pre-IND consultation is possible. The procedure is similar to other countries.
Domestic sponsors are not used to it. Multinational sponsors are not likely to take the
pre-IND consultation route either. I will explain a traditional IND process. The
sponsor sends its Korean agent (branch office or CRO) the IMPD (Investigational
Medicinal Product Dossier), investigator’s brochure (IB), protocol, ICF, GMP certificate,
and chemical analysis certificate. The Korean agent holds one or two informal
meetings with KFDA reviewers to check if preclinical data meet KFDA’s requirement.
IND preparation consists mainly of three activities: translation of protocol, ICF, IB
summary, and CMC for biologics; completion of KFDA templates with data abstracted
from the IMPD; and packaging and formatting. The IND application package is
electronically submitted. If no supplement is requested, KFDA approves the IND
application within 30 working days. KFDA usually requests supplement materials
related to preclinical data, and the IND approval decision takes three months on the
average. IRB submission can be parallel (see Figure 4). KFDA is going to start a
clinical trial notification (CTN) system next year after legislative action this year.
Adoption of the CTN system means that KFDA will recognize ICH region INDs. Under
the CTA system, the sponsor notifies KFDA of the trial after the IRB approval, and
starts the trial. Administrative details have to be worked out. But the CTN system
will substantially shorten the time to initiation of clinical trials (see Figure 5). Drugs
registered elsewhere in the world can be registered in Korea via a bridging process
(ICH E5, Ethnic Factors in the Acceptability of Foreign Clinical Data).
Korean GCP
Korean GCP was first adopted in 1987 and revised in 2000. It is based on the ICH GCP,
and is not much different. An unofficial English translation is available from the author.
English
Investigators are good in English. CRAs can read and write English with no difficulty.
But the conference call with multiple participants can always be uncomfortable to most
nonnative English speakers. SOPs, CRFs, and monitoring reports are all in English in
my company, as a majority of studies are from multinational sponsors and auditors from
abroad come to audit my company. Other Korean CROs may be similar to my company.
CRAs are familiar with multinational sponsors’ electronic data capture systems.
Connectivity
Korea is one of the most connected countries in the world by internet, mobile
communication, and high speed land transportation. Some sponsors want to check if
clinical trial sites are equipped with ADSL connection. They are. Korea is the leader
in internet connection and electronic industry. More than 95 percent of Korean
households have high speed access to internet. All the hospitals will be connected via
optic fiber line by 2010. My office is connected via dedicated t-2 line (6.312 Mbps) for
example.
Clinical trial professionals
Most Korean CRAs (clinical research associates) are registered nurses or pharmacists.
There is a serious shortage of clinical trial professionals, particularly experienced CRAs
and monitors. Multinational pharmaceutical company and global CRO Korean branches
have raised CRA’s pay levels sky high. The CRA turnover rate in my company is high
at about 20-25%. Others may be the same. The number of IND trials in Korea is
expected to quadruple in next four to five years. The CRA shortage will persist for a
while.
Gateway to China
Although not official, China prefers to include Korea in the pivotal regional trial
including China. Similarities in genetic polymorphism between Korean and Chinese
may be an important reason. Here is an example. A multinational sponsor wanted to
register a diabetes mellitus drug in China. The Chinese government asked for a
Chinese trial including other Asian countries. The sponsor selected Korea, filed the
IND in Korea first, and filed the IND in China after the Korean IND approval. The
Chinese government approved the IND in time. Although the trial started late, and
twice as many patients were to be recruited in China, the trial is expected to be
completed at about the same time as Korea within the sponsor’s timeline. China is 27
times larger than Korea in population.
Gateway to Japan
Several European sponsors asked me about whether I can help organize clinical trials in
Japan. I believe it is possible. Because the Japanese authority accepts the data from
Korea as well as Taiwan now, I will propose to organize the trial involving Japan,
Taiwan and Korea for time and cost reasons. The European sponsor, however, has to
understand that the Japanese authority requires Japanese PK/PD data. PK/PD data
from expatriate Japanese can replace the required Japanese PK/PD data, but it is not
clear Korean PK/PD data can replace the required Japanese PK/PD data. We would not
have definite answers until we challenge the Japanese authority, which I am very much
interested in.
Future of clinical trials in East Asia
Japan, Korea, and China are committed to East Asian regional trials. For more details,
see Japan’s PMDA (Pharmaceutical and Medical Devices Agency) website
( www.pmda.go.jp and click Presentation files (PDF) are updated in the Website of "East
Asian Pharmaceutical Regulatory Symposium 2008”).
Cultural difference?
Korea has a short history of rigorous pivotal new drug trials. Clinical trial staffs are
unfamiliar with following SOPs yet. I have to often apologize to sponsors because my
staff is deviant from agreed procedures or does not respond in a timely manner. I want
to add a few words. If my staffs have answers to your query, they would respond to
you promptly. If not, they tend to sit silent until they find the answer. It is one of my
important daily chores to remind my staffs to respond promptly to the overseas sponsor
with the answer or with the reply “I do not have the answer. I will give you the answer
by ‘when’.” Another constant reminder to my staffs is “Think everything before the
trial begins. Once the trial starts, go only by the book. If not in the book, then stop
and ask.” It is improving although not quite there yet.
Rigorous multinational pivotal trials are new to Korea, and KFDA constantly updates
regulations and guidelines in its effort to improve clinical trial environment. There are
still problems. For example, required preclinical data for oncology drugs are not
different from non-oncology drugs. This has to change. Another example is the
informed consent form for pharmacogenetic tests. Study samples can be shipped to
central labs outside Korea, but according to the law, its result has to be revealed to the
participant if s/he demands the result. Sponsors oppose this provision. This may
have to be relaxed too. KFDA reviewers regularly are rotated, and IND reviewers can
change in the middle of IND review, causing delays to the dismay of IND applicants.
Despite these problems, KFDA tries hard to be timely and accommodate as much as
possible.
Korean investigators are GCP-trained, and can recruit patients in time. Clinical trial
sites are all equipped to meet complicated diagnostic and treatment requirements. The
IND time line is competitive, and other regulatory requirement such as SAE reporting is
compatible with ICH guidelines. Trials in Korea are not low-cost but cost-effective
and of the highest quality. Otherwise you would not see the fifty fold increase in
multinational IND trials in just nine years.