Regional Clinical Trial in Indonesia: Challenging yet ...ccs.ncgm.go.jp/050/060/idf-04/idf-04-02/Forum072005.pdf · - Papua, Southeast Sulawesi, and Nusa Tenggara Timur province

Regional Clinical Trial in Indonesia: Challenging yet

Promising

Marlinang D Siburian

© 2018 National Center for Global Health and Medicine 2

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© 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


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


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


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


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


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



Overseas Production Base

is now a possibility.



Indonesian Pharmaceutical

Market: Total Value >6.5

Billion USD Average Growth

12.5%Increase Demand

for Generic Drugs



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



(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)

12

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


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


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

14

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


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


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


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


CLINICAL TRIALSPROCESS FLOW

18

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


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


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


• 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


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