Antalya, Turkey
Bioequivalence, Dissolution, Biosimilarity From the “Chain Bridge” to other Bridges of the Pharmaceutical World Prof.Dr.A.Atilla Hıncal İDE Pharmaceutical Consultancy on Registration, Biopharmaceutics and Education Ltd Co Ankara, Türkiye Bioequivalence, Dissolution, Biosimilarity 25 April 2015, Antalya, Turkey Presenta(on Overview —  I. GENERAL INTRODUCTION —  II. RESEARCHES AND BUSINESS FOR BIOSIMILARS —  III. INFO FOR TURKISH PHARMACEUTICAL AND BIOPHARMACEUTICAL INDUSTRY —  IV. A FEW INFORMATION RELATED TO TURKISH R&D GRANTS —  V. TURKISH DRUG AND MEDICAL DEVICE AGENCY —  VI. ONE EXPERIENCE FOR THE R&D FOR BIOSIMILARSon —  VII.Conclusion I. INTRODUCTION Antalya, Turkey
Treatment Will Be Transformed by New And Exis(ng Mechanisms Bioequivalence, Dissolution, Biosimilarity 25 April 2015, Antalya, Turkey Treatment Will Be Transformed by New And Exis(ng Mechanisms Bioequivalence, Dissolution, Biosimilarity 25 April 2015, Antalya, Turkey Analysis on Increasing Numbers of Innova(ve New Medicines and Orphan Drugs (2004-­‐2012) & (2013-­‐2017) Bioequivalence, Dissolution, Biosimilarity 25 April 2015, Antalya, Turkey Spending Growth on Most Therapies Will Be Lower Through 2015 CAGR=Compound Annual Growth Rate Bioequivalence, Dissolution, Biosimilarity 25 April 2015, Antalya, Turkey Patent Protected Medicines & Generic Compe((on’ Compara(ve Figures (2010-­‐2016) Bioequivalence, Dissolution, Biosimilarity 25 April 2015, Antalya, Turkey II. RESEARCHES AND BUSINESS FOR BIOSIMILARS Antalya, Turkey
Biosimilars & BiobeYers —  Biosimilar: Recombinant protein therapeu(cs that resemble but are not iden(cal to the original or reference product, —  i.e., a generic biologic drug. —  Closely resembles reference product in safety, purity and potency. —  Shows no clinically meaningful differences. —  BiobeYer: Enhanced version of the reference product. Clinically meaningful differences are expected, —  i.e., a 2nd genera1on biologic drug —  PotenCally an improved product in terms of efficacy, dosing, potency, etc. Bioequivalence, Dissolution, Biosimilarity 25 April 2015, Antalya, Turkey Biosimilars Established Facts Regulation strategies and pathway established in the EU (and US) Experience gained and perspectives It takes more than 10 years and 1$Bn to bring an innovative product with a new active substance on the market Biologicals are more complex and expensive to develop than small entity drugs Can/will public sector cope with the continuously rising costs for the health care system
? Bioequivalence, Dissolution, Biosimilarity 25 April 2015, Antalya, Turkey Why the interest in biosimilars ? Bioequivalence, Dissolution, Biosimilarity 25 April 2015, Antalya, Turkey Advantages of Biosimilars 1. Can be developed faster than a new drug 2. Much smaller risk of failure for develoment programs 3. Easier on paCents and lowers healthcare costs (market is growing due to aging populaCon in many count) Bioequivalence, Dissolution, Biosimilarity 25 April 2015, Antalya, Turkey Barriers to Entry in the Biosimilar Sector 1. Requires the same development process as for biopharmaceuCcals * Small number of people with experience developing biopharmaceuCcals makes it difficult to start this business. 2. Prices are lower than for new drugs * Erning a profit from biosimilars is difficult for large companies because of their enormous fixed expenses. Bioequivalence, Dissolution, Biosimilarity 25 April 2015, Antalya, Turkey Roadmap to A Biosimilars Bioequivalence, Dissolution, Biosimilarity 25 April 2015, Antalya, Turkey Some Biosimilar Products Launched in Europe 2006-­‐ 2009 (Ims Data) Bioequivalence, Dissolution, Biosimilarity 25 April 2015, Antalya, Turkey Biosimilars Are Emerging Rapidly But Adop(on to Date is Limited ' CAGR=Compound Annual Growth Rate ' Bioequivalence, Dissolution, Biosimilarity 25 April 2015, Antalya, Turkey A Growing Share of All Medicines Are Biologic, with Biosimilars and Non-­‐original Biologic (NOB) Products Bioequivalence, Dissolution, Biosimilarity 25 April 2015, Antalya, Turkey Best Selling Biological Products in EU (2008-­‐2013) Bioequivalence, Dissolution, Biosimilarity 25 April 2015, Antalya, Turkey Today’s Concern Around the Biosimilars Medicines Bioequivalence, Dissolution, Biosimilarity 25 April 2015, Antalya, Turkey Biosimilar Business Examples Pipeline Progress Report Development Timelines for Biosimilar Medicines Compared to Originator Biological Products Bioequivalence, Dissolution, Biosimilarity 25 April 2015, Antalya, Turkey Biosimilar Business: Pipeline Progress Report 1 Bioequivalence, Dissolution, Biosimilarity 25 April 2015, Antalya, Turkey Biosimilar Business: Pipeline Progress Report 2 Bioequivalence, Dissolution, Biosimilarity 25 April 2015, Antalya, Turkey Biosimilar Business: Pipeline Progress Report 3 Bioequivalence, Dissolution, Biosimilarity 25 April 2015, Antalya, Turkey ııı. A FEW INFORMATION RELATED TO TURKISH PHARMACEUTICAL INDUSTRY * Pharma Profil * Pharma Growth * Turkey’s Posi(on in Global Market * Market Analysis * Case Study Antalya, Turkey
Analysis Of Pharma Growth in Major Countries Bioequivalence, Dissolution, Biosimilarity 25 April 2015, Antalya, Turkey Pharma Profils of Emerging Markets & TURKEY Bioequivalence, Dissolution, Biosimilarity 25 April 2015, Antalya, Turkey Turkey’s Posi(on in Global Ranking (2005-­‐2015) Bioequivalence, Dissolution, Biosimilarity 25 April 2015, Antalya, Turkey Countries Compara(ve Analysis for Medicine spending per capita and growth rates The Global Use of Medicines: Outlook through 2017. Report by the IMS Institute for Healthcare Informatics. Bioequivalence, Dissolution, Biosimilarity 25 April 2015, Antalya, Turkey The Long Life And Spend On Medicines’s Rela(on Bioequivalence, Dissolution, Biosimilarity 25 April 2015, Antalya, Turkey Turkish Pharma Market Analysis 2005-­‐2020 (Billion USD) from IMS Bioequivalence, Dissolution, Biosimilarity 25 April 2015, Antalya, Turkey ıv. A FEW INFORMATION RELATED TO TURKISH GOVERNMENT GRANTS Antalya, Turkey
Turkish Government Grants in Pharmaceu(cal Field (for th Universities, Research Institutes, Industry) Bioequivalence, Dissolution, Biosimilarity 25 April 2015, Antalya, Turkey In Turkey R&D spendings are progressively increased (2000-­‐2010) Bioequivalence, Dissolution, Biosimilarity 25 April 2015, Antalya, Turkey THE SCIENTIFIC AND TECHNOLOGICAL RESEARCH COUNCIL OF TURKEY —  Na(onal Academic Support Programme —  1001-­‐Sci&Technol Res. Projects Fund. Programm —  1002-­‐Short Term R&D Fund. Programme —  1003-­‐Primary Subjects R&D Fund. Programme —  1005-­‐ Nat New Ideas & Prod. R&D Fund. Programme —  1007-­‐Public InsCtuCons Res Fund. Programme —  3001-­‐StarCng R&D Projects Fund. Programme THE SCIENTIFIC AND TECHNOLOGICAL RESEARCH COUNCIL OF TURKEY —  Business/Industry Na(onal Programmes —  1515-­‐FronCer R&D Laboratory Support Programme —  1507-­‐SME RDI Grant Programme —  1505-­‐University-­‐Industry CollaboraCon Grant Programme —  1514-­‐Ventura Capital Funding Programme —  1511-­‐Res. Technol. Dev. Inn. Projects in Priority Areas G.P. —  1602-­‐TÜBİTAK Patent Support Programme —  1513-­‐Technology Transfer Offices Grant Programme V. TURKISH DRUG AND MEDICAL DEVICE AGENCY TÜRKİYE İLAÇ VE TIBBİ CİHAZ KURUMU (TITCK) Antalya, Turkey
Turkish Drug and Medical Device Agency Türkiye İlaç ve Tıbbi Cihaz Kurumu (TITCK) —  Regulatory System : —  the registration, —  marketing approval/authorisation, —  pricing of pharmaceuticals, —  legal classification, —  control of advertisement for pharmaceutical products —  inspection of pharmaceutical manufacturers, wholesalers and retail pharmacies. —
expert committees Bioequivalence, Dissolution, Biosimilarity 25 April 2015, Antalya, Turkey Turkish Drug and Medical Device Agency Türkiye İlaç ve Tıbbi Cihaz Kurumu (TITCK) —  The legal basis for the pharmaceutical sector in Turkey is the Act on Medicinal Products for Human Use from 1928, which has been updated via various amendments. Bioequivalence, Dissolution, Biosimilarity 25 April 2015, Antalya, Turkey Turkish Drug and Medical Device Agency Türkiye İlaç ve Tıbbi Cihaz Kurumu (TITCK) —  Ministry of Health regulations stipulate that product registration can only be granted to a firm registered in Turkey. Thus, any pharmaceutical product imported into Turkey should be registered in the name of a Turkish agent or a Turkish commercial entity. Prior registration by a competent authority such as EMA or FDA facilitates Turkish registration but is not a prerequisite [1]. Bioequivalence, Dissolution, Biosimilarity 25 April 2015, Antalya, Turkey Turkish Drug and Medical Device Agency Türkiye İlaç ve Tıbbi Cihaz Kurumu (TITCK) —  Overarching Guideline This guideline covers all biosimilar products: —  Biosimilar medicinal products guide EffecCve date: August 2008 www.iegm.gov.tr/Folders/The Laws/Biobenzer_Kilavuzu, 07.08.2008,Eng._4621062.pdf —  Turkey does not have any product-­‐specific guidelines. The overarching guideline above refers to EMA guidelines for informaCon regarding specific product types, e.g. G-­‐CSF, epoeCn, etc. Bioequivalence, Dissolution, Biosimilarity 25 April 2015, Antalya, Turkey Turkish Drug and Medical Device Agency Türkiye İlaç ve Tıbbi Cihaz Kurumu (TITCK) —  In Turkey, medicinal products, including biologics and biosimilars, can only be marketed once a marketing authorization has been issued by the Turkish Drug and Medical Device Agency. In order to understand the marketing authorization process in Turkey, it is important to understand how certain terms are defined by the TITCK -­‐MOH. Important terms include: —  1. “Medicinal products” 2. A “substance” 3. An “active substance” 4. A “registered medicinal product for human use” 5. A “biological drug” 6. A “biosimilar drug” or “biosimilar product” 7. A “designated or retained biological (medicinal) reference product” Bioequivalence, Dissolution, Biosimilarity 25 April 2015, Antalya, Turkey Turkish Drug and Medical Device Agency Türkiye İlaç ve Tıbbi Cihaz Kurumu (TITCK) —  Biologics In Turkey, to obtain approval of a new biological product, an applicant must submit a “full” application to the MOH. A “full” application involves providing sufficient information to demonstrate the quality, safety and effcacy of the new biological product for the indications requested. Bioequivalence, Dissolution, Biosimilarity 25 April 2015, Antalya, Turkey Turkish Drug and Medical Device Agency Türkiye İlaç ve Tıbbi Cihaz Kurumu (TITCK) —  Biosimilars In Turkey, to obtain approval of a “biosimilar product,” an applicant must submit an “abridged” application to the MOH. The “abridged” application must demonstrate that there are no signifcant differences in terms of the quality, safety or effcacy between the biosimilar product and a biological reference product. In addition, a sponsor of a biosimilar product must comply with the requirements of Annex I of the Turkish Regulation for Approval of Human Medicinal Products, the technical requirements of the European Pharmacopeia monographs and any additional general requirements related to biosimilar products described in the guidelines of the Committee for Human Medicinal Products (CHMP) and the International Committee for Harmonisation (ICH). Bioequivalence, Dissolution, Biosimilarity 25 April 2015, Antalya, Turkey Turkish Drug and Medical Device Agency Türkiye İlaç ve Tıbbi Cihaz Kurumu (TITCK) —  To demonstrate the “quality” of the biosimilar product, the “abridged” application must include complete and detailed information regarding the biosimilar product, including head-­‐to-­‐head comparability studies with the biological reference product. For example, a biosimilar applicant must provide (1) data demonstrating that the active substance of the biosimilar product exhibits molecular and biological similarity to the active substance of the biological reference product; (2) biological activity, immunochemical properties and physicochemical studies; (3) purity and impurity studies, including an impurity profle; (4) stability data; (5) in vitro dissolution studies; and (6) data demonstrating that the pharmaceutical form, strength and route of administration of the biosimilar product and the biological reference product are the same (if they are not the same, then additional data will need to be presented to show comparability). Bioequivalence, Dissolution, Biosimilarity 25 April 2015, Antalya, Turkey Turkish Drug and Medical Device Agency Türkiye İlaç ve Tıbbi Cihaz Kurumu (TITCK) —  In addition, in order to demonstrate safety and effcacy of the biosimilar product, an “abridged” application will need to provide data from pre-­‐clinical and clinical studies. Specifically, with respect to data from pre-­‐clinical studies, an applicant must provide in vivo data showing the comparability of the biosimilar product and the biological reference product with respect to: (1) at least one repeat dose toxicity study (up to four weeks); (2) local tolerance; and (3) PK and PD studies Bioequivalence, Dissolution, Biosimilarity 25 April 2015, Antalya, Turkey Turkish Drug and Medical Device Agency Türkiye İlaç ve Tıbbi Cihaz Kurumu (TITCK) —  Finally, a biosimilar applicant will need to present comparability data from clinical studies. Specifcally, a biosimilar applicant will need to present data from phase I PK and PD studies (the PK and PD studies can be combined provided that the PK/PD relationship is characterized) as well as phase III studies (for each indication for which approval is sought). No phase II clinical trials are required. The clinical trial data submitted can be data from clinical trials conducted outside of Turkey provided that the clinical studies were done with the approval from a competent authority (such as the FDA, EMA, etc.) and are comparative with the biological reference product. In addition, a risk management plan will also be required. Bioequivalence, Dissolution, Biosimilarity 25 April 2015, Antalya, Turkey What does it mean “Science Based Regulatory Affair” for Biosimilar R&D? THE PRELIMINARY STUDIES SHOULD BE DONE IN ORDER TO SHOW EQUIVALENCE OF ENOXAPARIN SODIUM (Test) TO LOVENOX (Reference) Case Study -­‐2013/2014 By İDE -­‐ Ankara Bioequivalence, Dissolution, Biosimilarity 25 April 2015, Antalya, Turkey COMPARISON OF ENOXAPARIN SODIUM (Test) & LOVENOX-­‐Aven(s (Reference)
—
—
—
—
—
—
—
—
—
—
—
—
—
—
CRITERION 1 Equivalence of physicochemical proper(es 1 Molecular Weight Determina(on by Size Exclusion Chromatography 2 Chain mapping 2.1CTA-­‐SAX 2.2 MALDI-­‐MS 2.3 RPIP-­‐UHPLC–QTOF-­‐MS 3 Overall composi(on analysis 3.1NMR 3.2 certain USP tests (1)13C NMR spectra (2)UV-­‐specific absorbance (3)Sodium content (4)SO42-­‐/COO-­‐ COMPARISON OF ENOXAPARIN SODIUM (Test) & LOVENOX-­‐Aven(s (Reference) —  CRITERION 2 —  Equivalence of heparin source material and mode of depolymeriza(on —  1 Heparin source material —  1.1 qPCR as evidence that heparin source is porcine —  1.2 heparin source material complies with USP —  2 Evidences in support mode of depolymeriza(on: cleavage by alkaline beta-­‐elimina(on of the benzyl ester deriva(ve of heparin —  2.1Natural disaccharide building blocks —  2.2 process-­‐related modified disaccharides COMPARISON OF ENOXAPARIN SODIUM (Test) & LOVENOX-­‐Aven(s (Reference) —  CRITERION 3 —  Equivalence of disaccharide building blocks, fragment mapping and sequence of oligosaccharide species —  1 composi(onal analysis —  1.1 exhausCve digesCon with heparinase I, II, III, analyzed with SAX-­‐
HPLC —  1.2 exhausCve digesCon with heparinase I, II, III, analyzed with RPIP-­‐
HPLC —  1.3 depolymerized with nitrous acid and analyzed with RPIP-­‐HPLC —  1.4 depolymerized with nitrous acid and analyzed with CE —  1.5 exhausCve digesCon with heparinase I, II, III, analyzed with CE —  1.6 exhausCve digesCon with heparinase I, II, III, analyzed with malditof ms COMPARISON OF ENOXAPARIN SODIUM (Test) & LOVENOX-­‐Aven(s (Reference) —  2 Equivalence in fragment mapping —  2.1 digest with heparinase I analyzed with SAX-­‐HPLC —  2.2 digest with heparinase I analyzed with RPIP-­‐HPLC —  3 Equivalence in sequence of oligosaccharide species —  Shorter oligosaccharide sequence by maldi-­‐tof-­‐ms. COMPARISON OF ENOXAPARIN SODIUM (Test) & LOVENOX-­‐Aven(s (Reference) —  CRITERION 4 —  Equivalence in biological and biochemical assays —  4.1 AnC-­‐FXa —  4.2 AnC-­‐FIIa —  4.3 APTT —  Criterion 5 —  Equivalence of in vivo pharmacodynamic profile —  1 AnC-­‐FXa concentraCon-­‐Cme —  2 AnC-­‐FIIa concentraCon-­‐Cme Roadmap to A Biosimilars Bioequivalence, Dissolution, Biosimilarity 25 April 2015, Antalya, Turkey Conclusion •  Treatment is already started to be transformed by new and existing •
•
•
•
•
•
•
•
mechaisms. Increasing number of innovative medicine and orphan drug Spending growth on therapies Development timelines for biosimilar medicines Growing shares of biologics/ biosimilars / NOB / Biobetter Advantages and barriers to entry in biosimilar sector Biosimilars launched in Europe Today’s concern around the biosimilars How the biopharmaceuticals affect the drug expenses? Antalya, Turkey
THANK YOU FOR YOUR KIND ATTENTION e.mail: atilla.hincal@ide-­‐cso.com THANK YOU FOR YOUR ATTENTION
e.mail: a(lla.hincal@ide-­‐cso.com Antalya, Turkey
How the Biopharmaceu(cals Affect the Drug Expenses Bioequivalence, Dissolution, Biosimilarity 25 April 2015, Antalya, Turkey v. THE SCIENTIFIC AND TECHNOLOGICAL RESEARCH COUNCIL OF TURKEY TÜRKİYE BİLİMSEL VE TEKNOLOJİK ARAŞTIRMA KURUMU (TÜBİTAK) Antalya, Turkey
— Prof.Dr.Imre Klebovich —  Semmelweiss University —  Faculty of Pharmacy —  Budapest , Hungary