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Evaluasi dari Produk

copy drug

Dipresentasikan oleh :
Rozi Abdullah
Sumber :
Presentasi Prof.dra.Arini Setiwati

Copy drug Product


Copy product membutuhkan
studi in vivo equivalence
(bioequivalence)
2. Copy product hanya test in vitro
equivalence (dissolution)
3. Copy product tidak
membutuhkan uji klinik
komparatif
1.

Apa itu Bioequivalence ?


Ada beberapa definisi :
1. Bioavailability
Jumlah obat dalam persentase
dosis yang diserap dan
mencapai sirkulasi sistemik
(bioavailable) dalam bentuk
tidak berubah / aktif

2.

Bioavailabilitas Absolut :
Jika dibandingkan dengan
produk intravena, yang memiliki

bioavailabilitas (BA)100 %
3. Bioavailabilitas Relative :
Jika dibandingkan dengan
produk non-iv
4. Bioequivalence (BE)
Kesetaraan bioavailabilitas dari
2 produk obat dengan
kesetaraan farmasi atau

Pharmaceutical equivalence
Jika kedua produk obat berisi zat
aktif yang sama dalam jumlah
yang sama dan bentuk sediaan
yang sama
6. Phramaceutical alternatif
Jika kedua produk obat berisi
molekul aktif yang sama tetapi
berbeda dalam bentuk kimia
(garam, ester,dll) atau dalam
bentuk sediaan (tablet,
capsule,dll)
5.

7.

Therapeutic equivalence (TE)


Kesetaraan efek therapeutik dari
2 produk obat

Alasan untuk melakukan studi


Bioequivalence (BE)
Biaya

perawatan kesehatan terus


meningkat, dan salah satu komponen
penting yang dapat dikurangi secara
substansial adalah biaya obat

Diperlukan pergantian obat originator


yg mahal dengan
copies generik yang lebih murah

Copy

generic dimaksudkan untuk


mengganti produk innovator

copy generik harus menjadi


kesetaraan terapi untuk merek
produk innovator
Kesetaraan terapi dapat tercapai
ketika copy generik bioequivalent
untuk merek produk innovator

Studi BE memperlihatkan
therapeutic equivalence
Konsentrasi

plasma dari obat,


yang equilibirium dengan
konsentrasi, di dalam reseptor
site, menentukan :
jumlah molekul obat di reseptor
site yang menghasilkan efek
terapi
Konsentrasi plasma dari obat
diatur oleh :
Absorpsi, distribusi, metabolisme

Setelah

molekul obat berada


didalam tubuh, distibusi,
metabolisme tetap konstan
dengan subjek yang sama
berbeda dalam konsentrasi
plasma. (efek terapi) :
adalah karena perbedaan jumlah
dari obat yang diserap, atau
dengan kata lain tergantung
pada bioavaibilitas obat

Efek terapi tergantung pada


bioavaibilitas produk obat

Oleh karena itu, Bioequivalence


berarti kesetaraan terapi

Copy drug membutuhkan Studi


Bioequivalence
Paling

penting :
- obat dengan margin safety yang
sempit
- penggunaan obat kritis :
Di indikasikan untuk kondisi serius
yang membutuhkan respon terapi
yang pasti
e.g. - antiinfectives
- obat kardiovaskuler
- dll.

Produk yang pengeluarannya


secara
terus-menerus atau produk yang
pengeluarannya dimodifikasi
( karena formulasi sulit)

Di 26 Januari 2012, Indonesia (BPOM)


menerbitkan daftar obat yang membutuhkan uji
BE :

1.

Produk yang segera dilepaskan


ke sistemic action, ada 88 APIs
dari golongan obat berikut :

Antidiabetes oral
Obat kardiovaskuler(obat jantung,
antihipertensi, antithrombotics,
obat hypolipidemic)
Antiinfective

Obat

CNS
Kontrasepsi hormonal (semuapermintaan WHO)
Obat untuk oeteoporosis
Obat untuk traktus urinarius
(Disfungsi ereksi & Benign Prostat
Hypertropy)
2. Produk yang pengeluarannya
dimodifikasi untuk systemic
action, termasuk produk enteric
-coated

Copy produk membutuhkan


hanya tes dissolution
Copy

drug tidak membutuhkan studi


equivalence in vivo
Perbedaan copy drug hanya dalam
kekuatan :
Ketika kekuatan tinggi sudah BE
dengan komparator kekuatan rendah
dapat dibandingkan kekuatan tinggi
menggunakan dissolution test, dengan
dissolution profil f250 sampai 3
perbedaan pH antara 1,2 dan 7,5

Copy product yang tidak


membutuhkan tes equivalence
Copy

produk dalam bentuk water


solution:
- untuk digunakan parenteral
(iv,im,dll)
- untuk digunakan oral
(syrup,elixir,tincture,dll)
-untuk digunakan untuk mata
atau telinga
-untuk digunakan untuk topical
-untuk inhalasi atau semprot

Copy

drug dalam bentuk bubuk


atau water solution
Copy drug dalam bentuk gas

Design dan pelaksanaan dari


studi BE
Etik
Studi BE adalah studi yang dilakukan di
manusia (clinical studies)
- design & pelaksanaan dari studi BE
harus mengikuti prinsip Good Clinical
Practice (GCP)
- protokol studi harus mempunyai
persetujuan etik sebelum memulai studi
- informed consent harus didapat dari
setiap subjek sebelum screening subjek

1)

2.

Design
- Randomized 2 way cross-over
subjek sama menerima kedua
produk obat

setiap subjek kontrolnya sendiri

design ini sangat kuat,


membutuhkan jumlah subjek
yang kecil
-wash out : 5 x t dari
pengukuran analyte ( utk

Singel-dose-studies (>sensitive
menentukan pengeluaran
substasi obat dari produk obat
untuk diserap)

3.

Subjek
- orang sehat
- umur : 18 55 tahun
- berat : normal (BMI 18-25 )

Jumlah subjek
Minimal

12 (biasanya kasus 18-24)


tergantung intrasubject variability & power of
study :
power =90%
80%
intrasubject 15.0%n=12
12
17.5%n=16
14
20.0%n=20
16
22.5%n=24
20
25.5%n=28
24
27.5%n=34
28
30.0%n=40
32
Scr umum :
Intra subject CV < 20% n<20 <16

Sampel darah
Waktu

sampling (12-18)
1
at time zero (baseline)
2-3 before Cmax
4-6 around Cmax (to estimate
Cmax)
5-8 after Cmax, until at least
3 x t
(to cover>80% dari fase
absorpsi)

5) Bagian bioanalytic dari studi BE


harus mengikuti prinsip GLP (Good
Laboratory Practice)
Lowest Limit of quantitation (LOQ) :
nilai terendah yang bisa dideteksi
dengan accuracy & precision
dengan 20% adalah :1/20 x Cmax
Pengukuran analyte:
Parent drug hanya dikeluarkan dari
bentuk sediaan (> sensitive untuk
diubah dalam formulasi)

6) Test & reference (comparator)


products
Semua produk dari BE studi harus
dipersiapkan sesuai dengan peraturan
GMP (Good Manufacturing Product)
Tes produk harus originate dari jumlah
sedikitnya 1/10 dari skala produksi,
atau 100.000 units atau lebih besar
Comparator:
produk diharapkan digantikan oleh
copy drug

Scr umum : produk innovator dalam


negara masing masing

Indonesian comparator products:


Innovator

product registered in

Indonesia
If this is not available choose
with following priority:
a. Registered in 1CH - and
associated countries
b. Proven BE to the innovator with
the closest results
c. prequalified by WHO

Design and Conduct of BE


Studies
1.
2.
3.
4.
5.
6.
7.
8.

Etics
Design
Subject
Blood Sampling
Follow GLP (Good Laboratory
Practice)
Test & Reference (comparator)
Products
BA Parameters
BE Criteria

7) BA parameter :
BA parameters to be compared :
AUCt & AUCinf (extent of
absorption)
Tmax (rate of absorption)
Cmax (extent and rate of
absorption)

8) BE criteria

AUC-ratio :

90% Cl = 80 -125% (in general)


(GM T/R)
= 90-111% (drugs with
narrow
margin of safety)

Cmax

ratio :

90% Cl = 80 -125% (in general)


(GM T/R)
= 75 -133% (accepted,
bec. of
larger variation)
GM = Geometric mean
T/R = Test / Reference

Highly variable drugs (HVD)


Drugs

with intrasubject CV 30%


Generally safe drugs with shallow DRCs :
drugs with point estimate of AUC and Cmax:
between 90 -110% and
the total sample size of the Initial BE study is
20 or pooled sample size of the Initial and addon subject studies is 30,
Dissolution rates of test & reference products
are equivalent at the 3 pH conditions
Can

use broadened BE limits for Cmax :

from 0.8 - 1.25 to 0.75-1.33

Statistical analysis
AUC

& Cmax logarithmic transformation

ANNOVA for 2 way cross-over (to account


for variatons in : period, sequence and
subjects)
Intra subject CV = MS resid x 100 %
t

max :

Descriptive statistics (usually)


If comparison required : nonparametric
statistics untransformed data

BE laboratories Requirements
(1)
Comprise of 2 part : - clinical
- bioanalytical
The bioanalytic part :
Management requirement
Technical requirements
Should

follow GLP (Good Lab Practice) & should


fulfill General Requirements for Competence of
testing & calibration laboratories:
ISO/IEC 17025 (SNI 19-17025-2005)
These are the most important requirment for
lab. accreditation by NAC (KAN)

BE laboratories Requirements
(2)
The

clinical part :

Management requirements
Technical requirements
Should

follow GCP (Good Clinical


Practice) principles : ICH - GCP E6
Will be certified by NRA

BE Laboratories Accreditation
(1)
Accreditation

of a laboratory means
a formal recognition of the laboratory
competence to perform the specified
functions
National Accreditation Committee (NAC)
is an independent committee in the
National
Standardization Body (NSB) which has
the
authority to perform the laboratory
accreditation

BE Laboratories - Accreditation (2)


The National Accreditation Committee
in each country is internationally
recognized, and The accreditation is
based on guide / standard and
recommendation issued by ISO
(International Organization for
Standardization)
Accreditation of a lab. by NAC based on ISO
means international recognition of the lab.
competence

BE Studies -ASEAN Harmonization


(1)

What should be harmonized :


1. Guideline
2. Comparators
3. BE laboratories accreditation

BE Studies - ASEAN Harmonization (2)


Objective :
1. ASEAN guideline:
to provide a unified standard for BE

studies in the ASEAN region in terms of


ethical and scientific quality;
The rights, safety and well-being of
study subjects are protected
The study data are credible

2. ASEAN comparators :
the same comparators should be used

BE Studies - ASEAN Harmonization (3)


Objective :
3. BE Laboratories
the studies should be carried out in BE labs
accredited by NAC (based on ISO/IEC
17025)
Mutual acceptance of the BE study data by
the NRAs in the ASEAN region (no need for
duplication in the importing countries)
NRAs = National reg Agency (BPOM)

Selection of ASEAN Comparator


Product (1):
(1) Innovator product
Multiple manufacturing sites of the
same
innovator registered in the country are
acceptable
(2) If the innovator is not registered in
the country, justification is required
from the generic company to prove its
interchange-ability with the registered
innovator (in vitro or in vivo).

Selection of ASEAN Comparator


Product (2):
(3). If innovator product cannot be identified, the
choice of comparator must be made carefully and
be comprehensively justified by the applicant.
The selection criteria of a "well selected
comparator" in order of preference are :
Approval in ICH and associated countries
-Pre-qualified by WHO
Additionally, well selected comparators must
conform to compendial quality standards, if
applicable.

List of ASEAN Comparator Products


:
The list is not necessary because
the principle of comparator
selection has been agreed by all
member countries, in accordance
with WHO Guidance in TRS 937,
2006, Annex 7.

BE laboratories
The

implementation of ISO/IEC 17025


was not agreed among ASEAN
country. Malaysia and Singapore
follow OECD (Organization for
Economic Co-operation and
Development).
Fortunately, inspection by NRAs using
checklists has been agreed
The GLP and GCP Inspection
checklists: were discussed at the
17th ACCSQ PPWG Meeting and
finalized at the next meeting.

The Importance of BE studies in


ASEAN countries :
ASEAN countries are mostly developing
countries & nonproducers of NCEs

very dependent on:


generic / copy products because of the
affordable price, but should have high
quality

BE studies become very important :


to assure that no more generic / copy
products below standard exists in the market

The Importance of BE Studies - ASEAN


Harmonization
Cost for a BE study in an accredited BE
laboratory is around USD 10.000 to 40,000 a substantial portion in the development
of
a generic / copy product

Mutual acceptance of the BE study data by


the NRAs
in the ASEAN region is very important
in exporting generic / copy products
among ASEAN countries

Summary (1)
BE study is required to show whether a
generic copy can be interchangeable
with the brand innovator product
BE studies are conducted in
accordance with GCP and GLP
principles, and the study drugs are
prepared according to GMP
The bioanalytic methods used to
measure the measured analyte in
plasma/serum should be validated

Summary (2)
The BE criteria : 90% Cl of AUCratio
= 80 -125%
BE studies are mostly required
for generic/copy prescription
products in oral solid dosage
forms
The comparator / reference
product: normally the innovator
product

Summary

(3)
The importance of BA/BE studies in
ASEAN countries :
to provide affordable generic /
copy products with high quality
(bioequivalent to the innovator
products) in developing countries
of ASEAN

Summary (4)
BE studies - ASEAN harmonization
Mutual acceptance of BE study data by NRAs
in ASEAN region
ASEAN guideline for BE studies. The first guideline
adopted EMEA 2001 guideline, which were endorsed
in July 2004
The newest guideline adopted EMA 2010 guideline,
which will be endorsed at the next Meeting
ASEAN comparators for BE studies - the list is not
necessary, because the principle of selection has
been agreed in July 2007
BE laboratories - the GLP and GCP Inspection
Checklists were finalized In the last ACCSQ meeting
in May 2013

THANK YOU