Regional Clinical Trial in Indonesia: Challenging yet
Promising
Marlinang D Siburian
© 2018 National Center for Global Health and Medicine 2
Disclaimer
These Power Point slides are the intellectual property of NCGM under the copyright laws.Used by permission. All rights reserved. NCGM and the NCGM logo are registeredtrademarks of the National Center for Global Health and Medicine.
© 2018 National Center for Global Health and Medicine
Indonesia is the largest island country in the world with 13,446
islands 6 large areas: Sumatera, Java,
Bali+NT, Borneo, Sulawesi, Maluku+Papua
Climate: tropical with high humidity
Rainy season: October-AprilDry season: March-September
3
Jakarta
Tokyo
Sumatera
JavaBali, NT
Borneo SulawesiMaluku, Papua
INDONESIAGEOGRAPHY
© 2018 National Center for Global Health and Medicine
The 4th most populous country with 261 million people. Half of the population concentrated in the Java island.
600 different ethnics. The Javanese is the largest ethnics with almost 40% of the total population.
Muslim, 87.18%
Christian, 6.96%
Catholic, 2.91%Hindu,
1.69%
Buddhist, 0.72%
Confucianist, 0.50% Other,
0.13%
Unstated, 0.38%
4
MuslimChristianCatholicHinduOther
Source: National Statistics 2010
Sumatera
JavaBali, NT
Borneo SulawesiMaluku, Papua
INDONESIAPOPULATION
© 2018 National Center for Global Health and Medicine
Decentralized systemThe primary care facility is the
Community Health Center (Puskesmas), available down to the sub district area.
MOH
34 Provincial Gov.
District Gov.
Sub-District Govt.
99 Referral hospitals
556 District hospitals
3,320 Community Health Center (with beds)
(Puskesmas)
POH
DOH
Total hospitals in Indonesia are 5,734 hospitals.
5
33 National hospitals
INDONESIAHEALTH SYSTEM
© 2018 National Center for Global Health and Medicine
OOP, 60%
Government, 39%
others, 1%
Health Expenditure
6
51.160.1 65.9
0.020.040.060.080.0
2014 2015 2016
National Health Insurance (BPJS
Kesehatan) initiated in 2014 and aim for
Universal coverage by 2019
PROCURE-MENT
INDONESIAHEALTH PROCUREMENT
© 2018 National Center for Global Health and Medicine 7
Negative List Seminar with JICA Jakarta (June 2016) and with Japanese companies (Sept 2016): Negative List Revision
The New Negative
Investment List 2016:
Presidential Regulation No
44/2016
© 2018 National Center for Global Health and Medicine 8
67% FDI Medical
equipment testing
facilities
100% FDIPharmaceuticals
raw materials
153 million USDEurope
10%
919 million USDChina60%
459 million USDIndia30%
Source of APIs: 95% of Active
Pharmaceuticals Ingredients (APIs) are
importedTotal market value >1.5
Billion USDSource: Quintiles; Pharmaboardroom.com
Negative List Seminar with JICA Jakarta (June 2016) and with Japanese companies (Sept 2016): Negative List Revision
© 2018 National Center for Global Health and Medicine 9
Overseas Production Base
is now a possibility.
Negative List Seminar with JICA Jakarta (June 2016) and with Japanese companies (Sept 2016): Negative List Revision
© 2018 National Center for Global Health and Medicine 10
Indonesian Pharmaceutical
Market: Total Value >6.5
Billion USD Average Growth
12.5%Increase Demand
for Generic Drugs
Negative List Seminar with JICA Jakarta (June 2016) and with Japanese companies (Sept 2016): Negative List Revision
© 2018 National Center for Global Health and Medicine 11
49% FDI for Medical Equipment/Devices with Permits from
MOHDental
products2%
Orthopedic
Implants6%
Auxiliary Equipme
nt6%
Consumables23%
Others30%
Diagnostic imaging
33%
Medical Device Market ShareAnnual market growth for medical devices is 13%. Diagnostic imaging
holds 33% of the total market share.
Source: Quintiles; Pharmaboardroom.com
Negative List Seminar with JICA Jakarta (June 2016) and with Japanese companies (Sept 2016): Negative List Revision
© 2018 National Center for Global Health and Medicine
(1) Inadequate disease surveillance systems,
(2) Geographical barriers - 250 million people distributed in more than 17,000 islands;
(3) Limited testing facilities - large proportion of people remaining undiagnosed
(Mulyono, 2018)
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Testing device Point-of-careRDT (Rapid Diagnostic Test)
• Low cost• Easy to use• High specificity
and sensitivity
NON COMMUNICABLE DISEASES (NCDs) have emerge as major health problems in particular due to the
changes in the societies’ lifestyles.
INFECTIOUS DISEASECURRENT STATUS
© 2018 National Center for Global Health and Medicine 13
MALARIA
Source: Malaria Elimination in SEA, 2014
0.000.100.200.300.400.500.600.700.80
Aceh
Sum
ater
a U
tara
Sum
ater
a Ba
rat
Riau
Jam
biSu
mat
era
Sela
tan
Beng
kulu
Lam
pung
Bang
ka B
elitu
ngKe
pula
uan
Riau
DKI J
akar
taJa
wa
Bara
tJa
wa
Teng
ahDI
Yog
yaka
rta
Jaw
a Ti
mur
Bant
en Bali
Nus
a Te
ngga
ra B
arat
Nus
a Te
ngga
ra T
imur
Kalim
anta
n Ba
rat
Kalim
anta
n Te
ngah
Kalim
anta
n Se
lata
nKa
liman
tan
Tim
urSu
law
esi U
tara
Sula
wes
i Ten
gah
Sula
wes
i Sel
atan
Sula
wes
i Ten
ggar
aGo
ront
alo
Sula
wes
i Bar
atM
aluk
uM
aluk
u U
tara
Papu
a Ba
rat
Papu
a
TUBERCULOSIS
API<< 0.85 8 million people living in high risk area1st line medication: ACTs (Artemisinin-
based combination therapies)(MOH, 2015)
Low prevalence of resistance 1-2% (Lampung, 2016)
Sumatera Java Bali, NT Borneo Sulawesi Maluku,
Papua
2nd rank in the worldIncidence 399 per 100,000 people
MDR TB 12% from former casesHIV-TB 6.2%
MDR TB success rate 54%Bedaquiline (Sirturo) phase III study
ongoing(WHO, 2015)
%
Sumatera
JavaBali, NT
Borneo Sulawesi
Maluku, Papua
© 2018 National Center for Global Health and Medicine
0
10
20
30
40
50
60
Aceh
Sum
ater
a U
tara
Sum
ater
a Ba
rat
Riau
Jam
biSu
mat
era
Sela
tan
Beng
kulu
Lam
pung
Bang
ka B
elitu
ngKe
pula
uan
Riau
DKI J
akar
taJa
wa
Bara
tJa
wa
Teng
ahDI
Yog
yaka
rta
Jaw
a Ti
mur
Bant
en Bali
Nus
a Te
ngga
ra B
arat
Nus
a Te
ngga
ra T
imur
Kalim
anta
n Ba
rat
Kalim
anta
n Te
ngah
Kalim
anta
n Se
lata
nKa
liman
tan
Tim
urSu
law
esi U
tara
Sula
wes
i Ten
gah
Sula
wes
i Sel
atan
Sula
wes
i Ten
ggar
aGo
ront
alo
Sula
wes
i Bar
atM
aluk
uM
aluk
u U
tara
Papu
a Ba
rat
Papu
a
B C
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HEPATITIS B/C
620.000 HIV cases, 13% had antiretroviral
HIV-AIDS
HBV prevalence 2.5-10%HCV prevalence 1%
(Mulyono, 2018)%
Sumatera
JavaBali, NT
Borneo Sulawesi Maluku, Papua
Sumatera Java Bali, NT Borneo Sulawesi Maluku,
Papua
© 2018 National Center for Global Health and Medicine 15
AMR
National data not available
0102030405060708090
E. coli E. faecalis E. faecium
Anti-30S Anti-50S Fluoroquinolones
Cephalosporins
Penicillin
(Isolated from chicken poultry, SEA, 2014)
70% resistance to levofloxacin or ciprofloxacin (in Indonesia it is used as 1st choice to treat both lower and upper UTIs (Urinary tract infections), cheap-broad spectrum-readily
available)).
Fosfomycin resistance <20% in E. coli & K. pneumoniae
Meropenem resistance 21.3% in K. pneumoniae
© 2018 National Center for Global Health and Medicine 16
Neglected Tropical
Diseases (NTDs)
Soil-transmitted helminth (STH)
195 million people—live in STH-endemic areasRegular and periodic deworming with either
Albendazole or mebendazoleDefecation and hand-washing practices
Schistosomiasis
Caused by Schistosoma japonicumIn the province of Central Sulawesi
Praziquantel MDA (mass drug administration) by 2020
Lymphatic Filariasis
125 million Indonesians are at risk for acquiring LFHighest prevalence rates in Maluku, Papua in Eastern
IndonesiaDEC and Albendazole MDA
Coverage is only approximately 30%
Neglected Bacterial Infections
Leprosy, yaws, leptospirosis, and rickettsia infections.
Leprosy - Java (East, Central, and West Java)Yaws - Papua, Southeast Sulawesi, and Nusa
Tenggara Timur province Leptospirosis, and rickettsia – widespread,
no data
Neglected Viral InfectionsDengue
• 2nd largest number of cases worldwide• Approx. 3000 deaths annually
Chikungunya and Japanese encephalitis - no disease burden
© 2018 National Center for Global Health and Medicine 17
Refer to ICH GCP
Require IRB, BPOM (National Food and Drug Control Agency), and MOH approvals
Trials involving drugs already approved for marketing are NOT REQUIRED to apply for
approval (except for claiming new indications) continue to drug
registration
Inspection is done by regulatory authorities
All biological materials are NOT ALLOWED to be sent abroad, except if the assays could not be performed by local labs
CLINICAL TRIALSREGULATIONS
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CLINICAL TRIALSPROCESS FLOW
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Team Set Up
IRB Approval
MOH Approval CT End of Trial
Pharmaceuticals, Academic,
Hospitals, CROIRB
*) Documents:A. CT docs (must be in Bahasa Indonesia, except for multiregional CT)- CT protocol- IB- Inform Consent- Form I (CT Application Form to BPOM)B. Testing product docs- Testing product information- Certificate of Analysis (CoA)- Certificate of GMP- Summary Batch Protocol (3 batch in sequence)
for biological product (incl. Vaccine)- Lot release (for vaccine only)C. Other related docs- PI’s certificate of GCP- Contract with CRO (if applicable)- Insurance (If applicable)- Certificate of Laboratory (If applicable)- CV of PI
- CT Protocol- Safety plan- Monitoring plan- Data Management Plan- Training plan- Contracts- MoU- MoA- MTA
National IRB
• Approval from registered IRB
• Approval from BPOM • MTA (if applicable)
Monitoring:• Status report• Amendments?• Audit/visit vendor• Review contract• Ongoing supply IP
• Maintenance of blinding• Shelf life change• Routine – onsite / central
monitoring• Additional training?• Adverse events?
• IB update• Data entry• Data queries• Electronic data transfer
Patients recruitment
Organizational structure:• Sponsor• Chief Investigator• Trial management team• Host institution• Trial Steering Committee• Data Monitoring Committee• Endpoint Adjudication Committee• Coordinating center(s)• Central laboratory(ies)
20 days
2-4 weeks
• SAS approval –1 month
• SAS (Special Access Scheme) application to BPOM
Team set up Local IRB Approval BPOM Approval MOH Approval Start CT
BPOM Approval
• SAS approval –Import product
2-3 months for approval
© 2018 National Center for Global Health and Medicine
CROs:National Centers:
Medical Faculties with Academic Hospitals:
72 medical schools, 32 of them have been accredited A or B
Until 2014, there were 110.776 GPs and 19.367 specialists in Indonesia
19
IRBs:
55 IRBs registered in the National IRB
11 IRBs recognized by the FERCAP (Forum for Ethical Review Committees in Asia and the
Western Pacific)
INA-RESPOND (The Indonesia Research Partnership on Infectious
Disease): • Persahabatan Hospital, Jakarta;
• Prof. Dr. Sulianti Saroso Infectious Diseases hospital, Jakarta;
• Dr. Hasan Sadikin hospital, Bandung; • Dr. Kariadi hospital, Semarang; • Dr. Soetomo hospital, Surabaya;
• Sanglah hospital, Bali; • Dr. Sardjito hospital, Yogyakarta;
• Dr. Wahidin Sudirohusodo hospital, Makassar;
• Gatot Subroto Army hospital, Jakarta; • H. Adam Malik hospital, Medan
• Eijkman Institute, Jakarta
© 2018 National Center for Global Health and Medicine
NCDs39%
IDs19%
Pediatric5%
Geriatric1%
Psychiatric4%
Others32%
Local Academic
25%
Local Academic + Int. collaborator
23%
MNC36%
Local company
16%
20
There are 297 registered CTs in Indonesia. Most CTs were on NCDs and IDs and were
done by the Multi National Company (MNC) pharmaceuticals.
CLINICAL TRIALSCURRENT STATUS
© 2018 National Center for Global Health and Medicine 21
• Trial cost <<• “Less strict” regulations
• Wide variety of diseases NCDs, IDs, NTDs
• Research subjects >>• Muslim's market
• Capable and qualified manpower• Economic growth middle income
country (GDP growth 5.3%)• Economic cooperation between Japan-
Indonesia
Opportunities
• Less standardized IRBs - Accreditation of IRBs
• Lack of insurance companies -National Health Insurance
• Geographic disparity - infrastructure constructions, Community Health
Center
Challenges
© 2018 National Center for Global Health and Medicine 22
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