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.