evaluasi dari products copy drug
DESCRIPTION
Evaluasi Drug CopyTRANSCRIPT
![Page 1: Evaluasi Dari Products Copy Drug](https://reader035.vdocuments.pub/reader035/viewer/2022062502/55cf8e2e550346703b8f67df/html5/thumbnails/1.jpg)
Evaluasi dari Produk “copy drug”
Dipresentasikan oleh :Rozi AbdullahSumber :
Presentasi Prof.dra.Arini Setiwati
![Page 2: Evaluasi Dari Products Copy Drug](https://reader035.vdocuments.pub/reader035/viewer/2022062502/55cf8e2e550346703b8f67df/html5/thumbnails/2.jpg)
Copy drug Product 1. 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
![Page 3: Evaluasi Dari Products Copy Drug](https://reader035.vdocuments.pub/reader035/viewer/2022062502/55cf8e2e550346703b8f67df/html5/thumbnails/3.jpg)
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
![Page 4: Evaluasi Dari Products Copy Drug](https://reader035.vdocuments.pub/reader035/viewer/2022062502/55cf8e2e550346703b8f67df/html5/thumbnails/4.jpg)
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 alternatif farmasi dalam dosis molar yang sama
![Page 5: Evaluasi Dari Products Copy Drug](https://reader035.vdocuments.pub/reader035/viewer/2022062502/55cf8e2e550346703b8f67df/html5/thumbnails/5.jpg)
5. Pharmaceutical equivalenceJika kedua produk obat berisi zat aktif yang sama dalam jumlah yang sama dan bentuk sediaan yang sama
6. Phramaceutical alternatifJika kedua produk obat berisi molekul aktif yang sama tetapi berbeda dalam bentuk kimia (garam, ester,dll) atau dalam bentuk sediaan (tablet, capsule,dll)
![Page 6: Evaluasi Dari Products Copy Drug](https://reader035.vdocuments.pub/reader035/viewer/2022062502/55cf8e2e550346703b8f67df/html5/thumbnails/6.jpg)
7. Therapeutic equivalence (TE)Kesetaraan efek therapeutik dari 2 produk obat
![Page 7: Evaluasi Dari Products Copy Drug](https://reader035.vdocuments.pub/reader035/viewer/2022062502/55cf8e2e550346703b8f67df/html5/thumbnails/7.jpg)
Alasan untuk melakukan studi Bioequivalence (BE)Biaya perawatan kesehatan terus
meningkat, dan salah satu komponen penting yang dapat dikurangi secarasubstansial adalah biaya obat ↓
Diperlukan pergantian obat originator yg mahal dengan copies generik yang lebih murah
↓
![Page 8: Evaluasi Dari Products Copy Drug](https://reader035.vdocuments.pub/reader035/viewer/2022062502/55cf8e2e550346703b8f67df/html5/thumbnails/8.jpg)
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
![Page 9: Evaluasi Dari Products Copy Drug](https://reader035.vdocuments.pub/reader035/viewer/2022062502/55cf8e2e550346703b8f67df/html5/thumbnails/9.jpg)
Studi BE memperlihatkan therapeutic equivalenceKonsentrasi 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 dan eksresi (ADME) dari obat aktif
![Page 10: Evaluasi Dari Products Copy Drug](https://reader035.vdocuments.pub/reader035/viewer/2022062502/55cf8e2e550346703b8f67df/html5/thumbnails/10.jpg)
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
↓
![Page 11: Evaluasi Dari Products Copy Drug](https://reader035.vdocuments.pub/reader035/viewer/2022062502/55cf8e2e550346703b8f67df/html5/thumbnails/11.jpg)
Efek terapi tergantung pada bioavaibilitas produk obat
↓ Oleh karena itu, Bioequivalence
berarti kesetaraan terapi
![Page 12: Evaluasi Dari Products Copy Drug](https://reader035.vdocuments.pub/reader035/viewer/2022062502/55cf8e2e550346703b8f67df/html5/thumbnails/12.jpg)
Copy drug membutuhkan Studi BioequivalencePaling penting :
- obat dengan margin safety yang sempit- penggunaan obat kritis :
Di indikasikan untuk kondisi serius yang membutuhkan respon terapi yang pastie.g. - antiinfectives
- obat kardiovaskuler - dll.
![Page 13: Evaluasi Dari Products Copy Drug](https://reader035.vdocuments.pub/reader035/viewer/2022062502/55cf8e2e550346703b8f67df/html5/thumbnails/13.jpg)
- Produk yang pengeluarannya secara
terus-menerus atau produk yang pengeluarannya dimodifikasi
( karena formulasi sulit)
![Page 14: Evaluasi Dari Products Copy Drug](https://reader035.vdocuments.pub/reader035/viewer/2022062502/55cf8e2e550346703b8f67df/html5/thumbnails/14.jpg)
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
![Page 15: Evaluasi Dari Products Copy Drug](https://reader035.vdocuments.pub/reader035/viewer/2022062502/55cf8e2e550346703b8f67df/html5/thumbnails/15.jpg)
Obat CNSKontrasepsi hormonal (semua-
permintaan WHO)Obat untuk oeteoporosisObat untuk traktus urinarius
(Disfungsi ereksi & Benign Prostat Hypertropy)
2. Produk yang pengeluarannya dimodifikasi untuk systemic action, termasuk produk enteric -coated
![Page 16: Evaluasi Dari Products Copy Drug](https://reader035.vdocuments.pub/reader035/viewer/2022062502/55cf8e2e550346703b8f67df/html5/thumbnails/16.jpg)
Copy produk membutuhkan hanya tes dissolution Copy drug tidak membutuhkan studi
equivalence in vivoPerbedaan copy drug hanya dalam
kekuatan :Ketika kekuatan tinggi sudah BE dengan komparator kekuatan rendah dapat dibandingkan kekuatan tinggi menggunakan dissolution test, dengan dissolution profil f2≥50 sampai 3 perbedaan pH antara 1,2 dan 7,5
![Page 17: Evaluasi Dari Products Copy Drug](https://reader035.vdocuments.pub/reader035/viewer/2022062502/55cf8e2e550346703b8f67df/html5/thumbnails/17.jpg)
Copy product yang tidak membutuhkan tes equivalenceCopy 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 hidung
![Page 18: Evaluasi Dari Products Copy Drug](https://reader035.vdocuments.pub/reader035/viewer/2022062502/55cf8e2e550346703b8f67df/html5/thumbnails/18.jpg)
Copy drug dalam bentuk bubuk atau water solution
Copy drug dalam bentuk gas
![Page 19: Evaluasi Dari Products Copy Drug](https://reader035.vdocuments.pub/reader035/viewer/2022062502/55cf8e2e550346703b8f67df/html5/thumbnails/19.jpg)
Design dan pelaksanaan dari studi BE1) 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
![Page 20: Evaluasi Dari Products Copy Drug](https://reader035.vdocuments.pub/reader035/viewer/2022062502/55cf8e2e550346703b8f67df/html5/thumbnails/20.jpg)
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 t½ dari pengukuran analyte ( utk mengeluarkan >95% dari obat yg dimasukan pada pertama kali)
![Page 21: Evaluasi Dari Products Copy Drug](https://reader035.vdocuments.pub/reader035/viewer/2022062502/55cf8e2e550346703b8f67df/html5/thumbnails/21.jpg)
- 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 )
![Page 22: Evaluasi Dari Products Copy Drug](https://reader035.vdocuments.pub/reader035/viewer/2022062502/55cf8e2e550346703b8f67df/html5/thumbnails/22.jpg)
Jumlah subjekMinimal 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 32Scr umum : Intra subject CV < 20%→ n<20 <16
![Page 23: Evaluasi Dari Products Copy Drug](https://reader035.vdocuments.pub/reader035/viewer/2022062502/55cf8e2e550346703b8f67df/html5/thumbnails/23.jpg)
Sampel darahWaktu 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 t½ (to cover>80% dari fase
absorpsi)
![Page 24: Evaluasi Dari Products Copy Drug](https://reader035.vdocuments.pub/reader035/viewer/2022062502/55cf8e2e550346703b8f67df/html5/thumbnails/24.jpg)
![Page 25: Evaluasi Dari Products Copy Drug](https://reader035.vdocuments.pub/reader035/viewer/2022062502/55cf8e2e550346703b8f67df/html5/thumbnails/25.jpg)
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)
![Page 26: Evaluasi Dari Products Copy Drug](https://reader035.vdocuments.pub/reader035/viewer/2022062502/55cf8e2e550346703b8f67df/html5/thumbnails/26.jpg)
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
![Page 27: Evaluasi Dari Products Copy Drug](https://reader035.vdocuments.pub/reader035/viewer/2022062502/55cf8e2e550346703b8f67df/html5/thumbnails/27.jpg)
Indonesian comparator products:Innovator product registered in
Indonesia If this is not available → choose
with following priority:a. Registered in 1CH - and
associated countriesb. Proven BE to the innovator with
the closest resultsc. prequalified by WHO
![Page 28: Evaluasi Dari Products Copy Drug](https://reader035.vdocuments.pub/reader035/viewer/2022062502/55cf8e2e550346703b8f67df/html5/thumbnails/28.jpg)
Design and Conduct of BE Studies1. Etics2. Design3. Subject4. Blood Sampling5. Follow GLP (Good Laboratory
Practice)6. Test & Reference (comparator)
Products7. BA Parameters8. BE Criteria
![Page 29: Evaluasi Dari Products Copy Drug](https://reader035.vdocuments.pub/reader035/viewer/2022062502/55cf8e2e550346703b8f67df/html5/thumbnails/29.jpg)
7) BA parameter :
BA parameters to be compared :AUCt & AUCinf (extent of
absorption)Tmax (rate of absorption) Cmax (extent and rate of
absorption)
![Page 30: Evaluasi Dari Products Copy Drug](https://reader035.vdocuments.pub/reader035/viewer/2022062502/55cf8e2e550346703b8f67df/html5/thumbnails/30.jpg)
![Page 31: Evaluasi Dari Products Copy Drug](https://reader035.vdocuments.pub/reader035/viewer/2022062502/55cf8e2e550346703b8f67df/html5/thumbnails/31.jpg)
8) BE criteria AUC-ratio :
◦90% Cl = 80 -125% (in general) (GM T/R) = 90-111% (drugs with
narrowmargin of safety)
Cmax ratio : ◦90% Cl = 80 -125% (in general)◦(GM T/R) = 75 -133% (accepted,
bec. oflarger variation)
GM = Geometric meanT/R = Test / Reference
![Page 32: Evaluasi Dari Products Copy Drug](https://reader035.vdocuments.pub/reader035/viewer/2022062502/55cf8e2e550346703b8f67df/html5/thumbnails/32.jpg)
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 add-on 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
WHO TRS 937, 2006, Annex 7, p.373
![Page 33: Evaluasi Dari Products Copy Drug](https://reader035.vdocuments.pub/reader035/viewer/2022062502/55cf8e2e550346703b8f67df/html5/thumbnails/33.jpg)
Statistical analysisAUC & 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
![Page 34: Evaluasi Dari Products Copy Drug](https://reader035.vdocuments.pub/reader035/viewer/2022062502/55cf8e2e550346703b8f67df/html5/thumbnails/34.jpg)
BE laboratories – Requirements (1)Comprise of 2 part : - clinical - bioanalyticalThe 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)
![Page 35: Evaluasi Dari Products Copy Drug](https://reader035.vdocuments.pub/reader035/viewer/2022062502/55cf8e2e550346703b8f67df/html5/thumbnails/35.jpg)
BE laboratories – Requirements (2)The clinical part :
◦ Management requirements◦ Technical requirements
Should follow GCP (Good Clinical
Practice) principles : ICH - GCP E6Will be certified by NRA
![Page 36: Evaluasi Dari Products Copy Drug](https://reader035.vdocuments.pub/reader035/viewer/2022062502/55cf8e2e550346703b8f67df/html5/thumbnails/36.jpg)
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
![Page 37: Evaluasi Dari Products Copy Drug](https://reader035.vdocuments.pub/reader035/viewer/2022062502/55cf8e2e550346703b8f67df/html5/thumbnails/37.jpg)
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
![Page 38: Evaluasi Dari Products Copy Drug](https://reader035.vdocuments.pub/reader035/viewer/2022062502/55cf8e2e550346703b8f67df/html5/thumbnails/38.jpg)
BE Studies -ASEAN Harmonization (1)
What should be harmonized :1. Guideline2. Comparators3. BE laboratories accreditation
![Page 39: Evaluasi Dari Products Copy Drug](https://reader035.vdocuments.pub/reader035/viewer/2022062502/55cf8e2e550346703b8f67df/html5/thumbnails/39.jpg)
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 credible2. ASEAN comparators :
the same comparators should be used
![Page 40: Evaluasi Dari Products Copy Drug](https://reader035.vdocuments.pub/reader035/viewer/2022062502/55cf8e2e550346703b8f67df/html5/thumbnails/40.jpg)
BE Studies - ASEAN Harmonization (3)Objective :3. BE Laboratoriesthe studies should be carried out in BE labsaccredited 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)
![Page 41: Evaluasi Dari Products Copy Drug](https://reader035.vdocuments.pub/reader035/viewer/2022062502/55cf8e2e550346703b8f67df/html5/thumbnails/41.jpg)
Selection of ASEAN ComparatorProduct (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).
![Page 42: Evaluasi Dari Products Copy Drug](https://reader035.vdocuments.pub/reader035/viewer/2022062502/55cf8e2e550346703b8f67df/html5/thumbnails/42.jpg)
Selection of ASEAN ComparatorProduct (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.
![Page 43: Evaluasi Dari Products Copy Drug](https://reader035.vdocuments.pub/reader035/viewer/2022062502/55cf8e2e550346703b8f67df/html5/thumbnails/43.jpg)
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.
![Page 44: Evaluasi Dari Products Copy Drug](https://reader035.vdocuments.pub/reader035/viewer/2022062502/55cf8e2e550346703b8f67df/html5/thumbnails/44.jpg)
BE laboratoriesThe 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.
![Page 45: Evaluasi Dari Products Copy Drug](https://reader035.vdocuments.pub/reader035/viewer/2022062502/55cf8e2e550346703b8f67df/html5/thumbnails/45.jpg)
The Importance of BE studies inASEAN 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
![Page 46: Evaluasi Dari Products Copy Drug](https://reader035.vdocuments.pub/reader035/viewer/2022062502/55cf8e2e550346703b8f67df/html5/thumbnails/46.jpg)
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
![Page 47: Evaluasi Dari Products Copy Drug](https://reader035.vdocuments.pub/reader035/viewer/2022062502/55cf8e2e550346703b8f67df/html5/thumbnails/47.jpg)
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
![Page 48: Evaluasi Dari Products Copy Drug](https://reader035.vdocuments.pub/reader035/viewer/2022062502/55cf8e2e550346703b8f67df/html5/thumbnails/48.jpg)
Summary (2)The BE criteria : 90% Cl of AUC-
ratio = 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
![Page 49: Evaluasi Dari Products Copy Drug](https://reader035.vdocuments.pub/reader035/viewer/2022062502/55cf8e2e550346703b8f67df/html5/thumbnails/49.jpg)
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
![Page 50: Evaluasi Dari Products Copy Drug](https://reader035.vdocuments.pub/reader035/viewer/2022062502/55cf8e2e550346703b8f67df/html5/thumbnails/50.jpg)
Summary (4)BE studies - ASEAN harmonization
Mutual acceptance of BE study data by NRAsin 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
![Page 51: Evaluasi Dari Products Copy Drug](https://reader035.vdocuments.pub/reader035/viewer/2022062502/55cf8e2e550346703b8f67df/html5/thumbnails/51.jpg)
THANK YOU