Regulatory Environment and Clinical Trials in South East Asia

Ellick Wong PhD

Vice President
Pharmaceutical Development Centre
Pharmacia Corp.
SINGAPORE

Abstract
South East Asia is a growing pharmaceutical market. The regulatory environment h
as
similar characteristics but drug registration requirements and processes differ
among the
countries. An ASEAN initiative to harmonize the requirements for drug registrati
on is
in progress. Many multi-national research-based pharmaceutical companies have be
gun
to conduct multi-center trials in their global drug development programs involvi
ng
Asian medical centers for faster patient recruitment to achieve faster drug deve
lopment.
In the recent years, there is a steady increase in clinical trial activities in
South East Asia.

Key words
Regulatory, drug registration, clinical trial, South East Asia, ASEAN

Introduction

The Association of Southeast Asian Nations (ASEAN) is a growing region in

South East Asia (SE Asia) with 10 member countries namely, Indonesia,
Malaysia, Philippines, Singapore, Thailand, Brunei Darussalam, Vietnam, Laos,
Myanmar and Cambodia. The ASEAN region has a population of about 500
million, a total area of 4.5 million square kilometers, a combined gross domesti
c
product of US$737 billion, and a total trade of US$ 720 billion. The
pharmaceutical market in SE Asia is relatively small but the region remains
attractive to the pharmaceutical industry due to its growth potentials. Among th
e
ten ASEAN members, the five founding member countries (Singapore, Malaysia,
Thailand, Philippines & Indonesia) are more progressive with drug registration
and drug development clinical trial activities. This review will therefore confi
ne
the discussion on the regulatory environment, drug registration and clinical tri
al
developments in the 5 countries. Some key demographic and economic
performance figures for the countries are given in Table 1.
Table 1. South East ASIA1,02527.0%
1.0629.7%
7802.0%
3082.3%
2413.4%
PharmaMarket (MUSD)
Y2001Growth Rate
(2001/2000) LCD7302.5%
9533.9%
1,9503.0%
3,8404.5%
27,3505.0%
GDP/head (USD)
Growth Rate (2002)
209.678.462.423.84.0Population (Million)
IndonesiaPhilippinesThailandMalaysiaSingaporeCountriesSource : ECN, IMS

Regulatory Environment in SE Asia

The regulatory environment in the SE Asian countries has certain features that
are similar but, in general, there are differences in systems and practices. The
characteristics of the regulatory environment are listed in Table 2. Many of the
regulatory agencies in the countries suffer from having rather weak
infrastructures primarily due to limited human resources. Some of the agencies
have less than five staff in handling the registration matters of new drugs. As
a
result, the agencies traditionally performed mainly administrative work and simp
ly
endorse approvals of new drugs after other so-call advanced countries have
previously approved them. This has set the scene for the existing approval
systems in these counties relying heavily on the Free Sales Certificate or
Certificate of Pharmaceutical Product (CPP) issued by reference or advanced
countries for registration of new drugs.

Although there appears to be a lack of available scientific guidelines and very

few
of them have been established in the region, the ICH guidelines are well adapted
in most countries. Most countries still have the problem of lack of consistency
and transparency in the review procedure. In some countries we see
improvement as more direct communications are becoming possible between
regulator and the industry. The requirement of CPP from country of origin (COO)
still remains a key barrier to the registration of new drugs in the region.
Table 2. Regulatory Environment S.E. Asia
..Regulatory agencies: relatively weak infrastructure,
small resources, structurally different
..Diversity of regulatory processes / requirements
..Diversity of approval timelines
..Standards of scientific guidelines not well-established
..Lack of consistency & transparency but improving with
more dialogues with industry
..Requirement of CPP from COO or reference countries

The regulatory agencies in the SE Asia countries, listed in Table 3, have been
organized differently and some changes have taken place in the recent years.
The most significant change in the system was seen in Singapore. In 2001, the
Singapore agency was reorganized into a statutory board known as the Health
Sciences Authority that run in a corporative fashion. The agency has established
two centers to deal with drug registration; the Centre of Pharmaceutical
Administration (CPA) is the licensing body that performs administrative work
related to drug registration while the Centre of Drug Evaluation (CDE) to perfor
m
scientific and medical evaluations of new drug applications. The CDE has
established for the first time in-house capability for scientific and medical re
views
of submissions and provide regulatory consultations to the industry. However
partly due to the small number of staff available at the CDE, the center still h
ave
to rely heavily on external reviewers, many of them academic pharmaceutical
and medical scientists from the local university. Many other regulatory agencies
in SE Asia have similar constraint in in-house resources dealing with new drug
applications, the reviewing process involves external experts in their countries
at
some points.
Table 3. Regulatory Agencies in S.E. AsiaIndonesia :National Agency of Drug & Fo
od ControlMalaysia:Drug Control Authority, NCE UnitPhilippines:BFAD, DoHThailand
:ThaiFDA, Drug Control Div.
Singapore:Health Sciences Authority (HSA)
Centre for Pharmaceutical Admin. (CPA)
Centre for Drug Evaluation (CDE)

Dug Registration in SE Asia

In the region, drug registration processes vary considerably among the countries
with different sets of requirements for new drug approvals. From the past
experience, the approval timelines in the countries vary from 6 to 24 months.
The author has analyzed available in-house data on 6 new drugs recently
registered in the 5 ASEAN countries and the approval timelines are shown in
Figure 1. The data also allowed estimation of the ranges of registration timelin
es
in the countries to be made: Singapore and Thailand, 6-12 months, Indonesia
and the Philippines 12 ¡V18 months and Malaysia may take up to 2 years.

8.323.98.816.67.67.716.44.111.94.19.237.34.926.84.319.89.69.222.29.920.215.85.79
.57.20.05.010.015.020.025.030.035.040.0Singapor
MalaysiaThailandIndonesiaPhilippinesNo. of Months
Product AProduct BProduct CProduct DProduct EProduct FFigure 1. NCE Approval Tim
e

7.521.49.112.615.3
Registration Requirements

Table 4 shows the requirements of various regulatory and administrative

documents for new drug registration in the 5 countries. All countries require CP
P
and GMP certificates. All countries prefer to have CPP from COO, however for
Singapore, Indonesia and Thailand, CPP from selected countries other than
COO could be used. With the exception of Malaysia, all countries require CPP at
the point of filing. Table 5 shows more details on the CPP requirements and
timing of submission.

Indonesia authority would require additional Free Sales Certificate issued by an

advanced country. For Philippines and Thailand, the CPP and GMP certificates
would need to be legalized. Most countries also demand submission of copies
of manufacturing licenses of the manufacturers and packagers for products to be
registered. Because of cultural and religious reasons, Indonesia, Malaysia and
Philippines authorities require information on sources of all ingredients of ani
mal
origin. The Indonesian authority will not approve products containing any
ingredient of porcine source.

Indonesia
Malaysia
PhilippinesSingapore
ThailandRemarksRegulatory / Administrative
DocumentsCPP (COO)YYYYYMALAYSIA: CPP at Stage 3Ytrack IIGMP Certificates (Manufa
cturer &
Packager)
YYYYYNotarized & Legalized of above?YYYYYPatent InformationYYYYYYYYYYYINDONESIA
: porcine sources
not acceptable.
For ingredient of animal origin:
Declarations specifying the origin (animal
species)
Manufacturer's RegistrationTable 4. REGISTRATION REQUIREMENTS
Additional FSC (2)
Manufacturing license (Manufacturer &
Packager)
Info of manufacturers of ingredients

.
Table 5. CPP REQUIREMENTSSubmissionCOO is required for approval. Export certific
ate can be
used in place of a CPP from COO for submission, but
CPP from COO is required for approval.
PHILIPPINESSubmissionCOO ¡Vfor Track I and Track III
Track II ¡VAssessment Reports + 2 CPPs(EMEA &/or
countries with GES) or Assessment Reports + 3 CPPs
(countries with GES)
INDONESIASubmissionCOOTHAILANDStage 3COO (Manufacturer or final packager/ produc
t releaser)MALAYSIASubmissionCOO or from the recognized countries (with CPA¡¦s
permission)
SINGAPORERequired atCPP RequirementsCountry

Table 6 shows the other requirements for new drug registration. The common
files are formulation, manufacturing method, method of analysis and
specifications, cert of analysis, and stability report. The Philippines authorit
y
requires additional documents such as in-process control, validation documents
and plant descriptions. Most countries require samples of product, samples for
testing and working standards. All countries also would need to have proposal
for labeling and pack insert. Documents on pre-clinical, pharmacology,
toxicology, clinical pharmacology and clinical studies are standard requirements
.
The Malaysian and Thai authorities require additionally 3 published studies; thi
s
requirement has often presented difficulties for companies to fulfill and delay
the
registration.
Indonesia
Malaysia
PhilippinesSingapore
ThailandRemarksBasic CMC Documents
In Process ControlYYYFormulationYYYYYManufacturing MethodYYYYYMethod of Analysis
& SpecificationsYYYYYValidation Documents
YYYSingapore - Protocol, Reports
and Summary of Results.
Plant Facility DescriptionYYYYYYYYYYYPhilippines - numerical /
descriptive results.
YYYYYRegistration Samples
3522Samples for Analytical Testing with CoAYYYYYYYPackaging Materials
YYYYY35525YYYYYPre-Clinical & Clinical Documents
YYYYYPharmacology & Toxicology YYYYYPD / PK YYYYYYYYYClinical Documents YYYYYPub
lished Clinical Papers33Visual Samples (Commercial Packs) with
Original CoASamples of Working standards
Pre -Clinical Documents
Bioavailability study reportTable 6. REGISTRATION REQUIREMENTS
Proposal for labeling (artwork; carton,
labels, blisters, package insert)
No. of sets requiredCoA for each excipientsCoA of Final Product
Stability Report
Pack Insert

Regulatory Review and Approval Process

The review processes vary from country to country in the region. In Indonesia, a
pre-registration consultation should take place before formal submission of file
s.
The procedures are defined by three tracks. Track I is for orphan drugs or drugs
for treating life-threatening diseases. Track II and III are for products carryi
ng
different approval status. The agency sets target review timelines for Track I
at100 days, Track II at 150 days, and Track III at 300 days. For Track II produc
ts,
assessment reports are required on top of a CPP, although CPP from non-COO
is acceptable. The fee for registration is Indonesian Rupiah 20 million (about
US$2,000).

In Malaysia, the drug registration process is in 3 stages with different

documentations submitted at each stage. CPP from COO is submitted only at
Stage 3. This facilitates early new product filing in Malaysia while the product
is
under review by health authorities elsewhere, in COO and other advanced
countries. The registration fee is RM1000 (about US$300). The target review
timeline ranges 38 to 66 weeks.

In Thailand, after filing, the company can choose to make a formal presentation
to the agencies staff and medical reviewers on data submitted. After approval,
most new drugs are subjected to post-marketing surveillance (PMS) for several
years and hence the authority would demand PMS study protocol to be
submitted before product approval is granted. The registration fee is Thai Baht
2,000 (about US$50). The target review timeline is 7 months.

In the Philippines, the agency may request the company to perform local
registration trial if there is no proof of the product¡¦s clinical use in more than
5,000 patients in the COO; even the product is approved in the COO. The fee for
product registration is around PhP 20,000 (about 400 USD) and the target review
timeline is 12 to 18 months.

In Singapore, since the establishment of the CDE, the submission of new drug
application via the so-called ¡¥CDE route¡¦ could be done prior to any approval of
the product elsewhere and hence one can file for new drug registration in
Singapore simultaneously as the NDA is filed in the COO or in other advanced
countries. The fee is in the region of S$8,000 (about US$4,500) for a file of
10,000 pages. More detailed fee structure for submission could be found in CDE
web-site
(http://www.hsa.gov.sg/hsa/CDE/CDE_service_directory_feesschedulefornda.htm). Ta
rget review timeline is 30 weeks.

In Singapore, one can also file product registration following a conventional ro

ute
of registration via the CPA office. As this route of filing demands the submissi
on
of CPP, this is only possible for products previously approved in COO or in othe
r
advanced countries. The registration fee is S$545 (about US$280) and the
target review timeline is 17 weeks. There is a fast track review route but the
authority requires assessment reports on the product from two advanced
countries.

ASEAN Regulatory Harmonization Initiative

A recent Centre of Medicine Research International survey (1) showed that most
international companies would prefer to submit registration files simultaneously
in
Asia when the NDA is submitted to the COO or other developed countries.
However due to various reasons, not many companies can achieve this goal and
certainly not with all their products. It is well recognized that there are stil
l many
regulatory barriers hindering simultaneous submission in SE Asia and the
diversity in requirements is one of the most important. In view of this, the ASE
AN
countries have started a harmonization initiative in 1999. The initiative, known
as
the ASEAN Consultative Committee for Standards and Quality ¡V Pharmaceutical
Product Working Group (ASEAN CCCSQ-PPWG), aimed at establishing
common technical requirements and to develop quality guidelines for product
registrations. When these documents are ready and be implemented in 2003 -
2004, the registration timelines in ASEAN will be significantly aligned.

While waiting for the ultimate harmonization to become a reality, the Singapore
agency HSA has been progressive in making international cooperation. HAS has
recently signed pact with the health authority of Australia, TGA. The cooperatio
n
is aiming at a better sharing of experiences and this will bring an improved
reviewing process to Singapore.

Clinical Trials in SE Asia

Asia is increasingly being recognized as an important base for R&D. Many multi-
national research-based pharmaceutical companies are beginning to see the
potential of Asia in contributing to drug development. Several companies and
CROs have established their trial monitoring organizations and built facilities
in
Asia to perform trials to international standards and meeting regulatory
requirements. The large patient pool available for trials in Asia has potential
for
faster patient recruitment, and hence trials involving Asia medical centers may
contribute to shortening the development time of new drugs. A recent review has
discussed the challenges and benefits of conducting drug development clinical
trials in SE Asia (2).

Many companies have already successfully conducted many drug development

global studies in SE Asia. With close clinical trial monitoring and professional
project management, many medical centers particularly those located in major
cities could perform high quality GCP studies and they often can compete very
favorably in terms of patient recruitment and costs with other centers in the
Europe, USA or Latin America.

For the past many years, although SE Asian countries had demonstrated their
capabilities in performing clinical trials, there were still many issues which
discouraged companies from bringing in Phase II and III studies to the region.
One of the issues was the long clinical trial approval process. It sometimes too
k
longer than 6 months for an approval to be granted in some countries and hence
limits their participation. With the joint efforts of industry, hospital and reg
ulatory
authorities, there has been a steadily improvement in shortening the timelines
lately. In some countries nowadays, IRB and regulatory submissions could be
done simultaneously and this has significantly improved the overall timeline for
new trial start-up. In general, the approval timeline now is 3 to 4 months in SE
Asia and for most trials it is acceptable for them to join. Table 7 shows the
average timelines for clinical trial approvals in the 5 ASEAN countries.
Table 7. Clinical Trial Approval Timelines in SE Asia6Y1659Philippines3N1469Thai
land3412No of
studies
N14105MalaysiaY13117IndonesiaN1138SingaporeParallel
(Y/N)
Approval
period
(weeks)
Regulatory
Approval
(median weeks)
IRB
Approval
(Median weeks)

In many of the SE Asian countries, the governments have identified the

biomedical/life sciences industry as a key segment for future economic growth.
Among them, the Singapore government has been particularly active in this area.
They offer support and financial incentives to pharmaceutical and biotechnology
companies to build research facilities and train manpower resources to develop
R&D. Figure 2 shows that the effort of the Singapore government in promoting
clinical trials in the past few years has really paid off. The number of clinica
l trials
reflected by the numbers of Clinical Trial Certificates applications to the heal
th
authority has increased exponentially over the past years. Also it is worth to n
ote
that majority of the trials conducted in Singapore these days are in Phase II an
d
III. In Singapore, the number of Phase I trials has also significantly increased
after two Phase I laboratories were established by multi-national pharmaceutical
companies recently.
Total no. of Clinical Trial Applications0204060801001201401601801978197919801981
198219831984198519861987198819891990199119921993199419951996199719981999200
2001YearNo.
of
ApplicationsFigure 2. Number of Clinical Trial Certificate
Applications in Singapore

Drug Trials Growing in AsiaDrug Trials Growing in AsiaSingaporeSingaporeSingapor

e ¡VClinical Trials (2001)Singapore Singapore ¡V¡VClinical Trials (2001)Clinical Trial
s (2001)
Phase IPhase IIPhase IIIPhase IV30% (50)
12% (19)17% (28)
41% (68)
Phase IPhase IIPhase IVPhase III
In the other ASEAN countries, the clinical trial activities have just begun. Tab
le 8
shows the number of clinical trial approvals issued by the authorities in Malays
ia,
Philippines and Indonesia in year 2000 and 2001. Although the numbers of trials
in Phase III are still rather low in these countries, there is a trend that the
numbers are increasing. It is foreseeable that SE Asia countries¡¦ contribution to
global drug development will grow from strength to strength in the near future.

Figure 8 . Clinical Trials in SE AsiaFigure 8 . Clinical Trials in SE AsiaFigure

8 . Clinical Trials in SE AsiaPhilippines85 (2000)100 (2001)
Indonesia(mainly phase IV)
Phase IVPhase III106 (2000)60 (2001)
23 (2000) 42 (2001)
29 (2000)53 (2001)
Phase IVPhase III8 (2000)9 (2001)
MalaysiaData provided by the health authorities in the respective countries

Global Drug Development and Simultaneous Drug Registration

The Centre of Medicine Research International conducted recently reported a

survey (3) they did with multinational pharmaceutical companies on their
involvement of Asian countries (ex-Japan) in conducting their drug development
trials. Based on the responses from 13 companies, 8 routinely conducted clinical
trials in Asian countries; all 8 companies used local trial data for regulatory
submissions. Three companies had conducted pivotal studies in Asia, and 2 of
them had included Asian data in their ICH submissions.

The results from the survey were indicative of some multinational research-based
pharmaceutical companies¡¦ strategy in including Asia in their globalised drug
development program. Increase in the participation in global drug development
programs by Asian medical centers will contribute to shorten development time
and to achieve simultaneous drug registration, and thereby to reach the goal
shared by all in drug industry and regulatory agencies: ensuring quicker access
to new and innovative medicines for all patients and to meet their medical needs
wherever they are.

References

1. Center of Medicine Research International, CMR Report, June 2001 (web-site:

www.cmr.org)

2. CF Fenn, E Wong, D Zambrano. The contemporary situation for the conduct

of clinical trials in Asia, Int. J. Pharm. Medicine 2001, 15: 169-173

3. Center of Medicine Research International, CMR R&D Briefing No 37.

December 2002 (web-site: www.cmr.org)