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DEVELOPMENT OF A BIOSIMILAR IN THE E.U Master 2 Réglementation du Médicament dans l’Union Européenne 2011-2012 Thierry AHADJI, Pablo APIOU, Matthieu BOULENGER, Caroline HABAUZIT, Marie VASSELIN Introduction Global sales of biological medicines have grown rapidly during the past 30 years With the patents expiry this market appeared as a significant target for generic companies However, if the economic issues are attractive the barriers to entry the market are important « Biosimilars offer new opportunities both for the growth of our generic industry and for the control of our national health expenditures » Günter Verheugen (April 2006) 2 Contents 1st part: Biosimilars outlines 2nd part: Should a generic company invest on biosimilars ? 3rd part: Developing a hCG Biosimilar 3 1st part: BIOSIMILARS OUTLINES 4 Legal environment Directive 2004/27/EC - Article 10: 2.(b) « generic medicinal product » same qualitative and quantitative composition in active substances and the same pharmaceutical form as the reference medicinal product, and whose bioequivalence with the reference medicinal product has been demonstrated by appropriate bioavailability studies. 4. « biosimilars » where a biological medicinal product which is similar to a reference biological product does not meet the conditions in the definition of generic medicinal products, owing to, in particular, differences relating to raw materials or differences in manufacturing processes of the biological medicinal product and the reference biological medicinal product, the results of appropriate preclinical tests or clinical trials relating to these conditions must be provided. 5 Variability “Key word” for Biologics products • Variability Linked to the molecule. Ex : Glycosylation profile • Variability Linked to impurities 6 Biosimilars are not biological generics! The references can not be compared Properties Biotech drugs Chemical drugs Size Large Small Structure Complex Simple Stability Unstable Stable Modification Many options Manufacturing Unique line of living cells. Predictable chemical process. Impossible to make Identical copy can be made. identical copy Characterization Impossible to characterize fully due to a mixture of related molecules Well-defined Easy to fully characterize 7 Biosimilars are not biological generics! Biosimilars are similar… … but not identical 8 Biosimilars are not biological generics! Chemical product Biological product Due to the complexity and variability of a biological, the quality profile (and hence the clinical profile) is determined by the manufacturing process. “The process makes the product” Generic Biosimilar: Many possible isoforms 9 Source : Afssaps « Des médicaments issus des biotechnologies aux biosimilaires : Etat des lieux » «The process makes the product» Ex: Variability induced in manufacturing changes for a commercial Mab Even originators are « manufacturing biosimilars » of their original products Worldwide experience with Biosimilars development (Marc Mc Camish and Gillian Woollett) – Landes Bioscience 10 Risks linked to the Quality profile changes • Viral safety: need evidence of lack of adventitious agents in the MCB (for recombinant proteins) • Variability and the potential changes in quality profile (detected or not) lead to the main problem for biosimilars (and biologicals) : IMMUNOGENICITY Immunogenicity may have serious clinical consequences (in case of neutralizing antibodies) Safety Efficacy (inhibition – up to complete loss – of the therapeutic effect) 11 Immunogenicity Nature Reviews – Drug discovery 12 Immunogenicity Example of immunogenicity related to quality: IFN alpha-2a (a) Lyoph.+ HSA Room temp. (b) Lyoph. + HSA Refrig. (c) Liquid + HSA, Refrig. (d) Liquid, HSA free, Refrig. (e) Lyoph. HSA free, Refrig It is not yet possible to fully predict the induction of antibodies The relative immunogenicity of therapeutic proteins can only be evaluated in clinical studies 13 Key issues All these possible differences between a biosimilar and its reference lead to 2 main questions: How can the level of similarity be well established ? How can the risks associated be defined ? Debate on substitutability 14 nd 2 part: SHOULD A GENERIC COMPANY INVEST ON BIOSIMILARS? 15 Current market • Limited market experience (Somatropine : 2006) • Highest number of approvals : Europe 14 approvals (but for only 3 Active substances) Somatropin 2006 EPO Filgrastim 2010 16 Opportunities: Biologics Market expansion Almost 100 Mds $ 80% of hospital prescriptions 12% of pharmaceutical market Several blockbusters 17 Opportunities: Biosimilars Market expansion Fierce competition from large generics Low price and faster market penetration is expected Biosimilars are experiencing high demand EPO G-CSF HGH Existing Biosimilars Emerging Biosimilars Insulins The high prevalence of diabetes is leading to the increased demand Biosimilars Market IFN Biosimilars are under development 2009 2015 Mabs Most awaited segment with immense opportunity. Significant target for biosimilars developpers Mabs Market size 36,4 Mds $ 60 Mds $ 18 Opportunities: Patents expiry From well-established biosimilar proteins… … to complexe large proteins biosimilars: Mabs 19 However… The actual european market of biosimilars is still limited ( < 20% of total sales where they are present) The market entry of biosimilars can't be compared to the market entry of generics Example of the French market: Note that in Germany the market entry of biosimilars is important, for instance, in 2009 EPO biosimilars represented 29% of the global EPO market 20 Substitutability issues Substitutability : “pharmacist 's ability to dispense a biosimilar rather than the reference drug” Overall GuideLine: « In order to support PharmacoVigilance monitoring, the specific medicinal product given to the patient should be clearly identified » It precludes automatic substitution NATIONAL COMPETENCES Automatic substitution not allowed France, Germany, Greece, Italy, Slovenia, Spain, Sweden, UK Automatic substitution must be actively prohibited by the physician Czech Republic Official list stating which products cannot be substituted Denmark, Finland, Hungary, Norway, Slovakia Physicians obliged to prescribe by brand name Austria 21 Should a generic company invest on biosimilars?: conclusion Strengths Weaknesses Development cost and duration compared with a « full dossier » Patents expiring Limited experience Devlopment Cost and duration compared with generics Substituability Opportunities Biologicals market size Future patents expiry Experience improvement Low prices will influence physician's prescription SWOT Threats Innovators experience Bad physicians’ point of view 22 3rd part: DEVELOPMENT OF A hCG BIOSIMILAR 23 Human Chorionic Gonadotrophin (hCG) •Glycoprotein hormone •Heterodimeric structure: 2 sub-units non covalently associated (held by hydrophobic forces) • 1 sub-unit α : 93 amino acids Common to LH, FSH, TSH • 1 sub-unit β : 145 amino acids Confers the biological specificity of the hormone 24 Human Chorionic Gonadotrophin (hCG) Mechanism of action: LH/CG-R (granulosa cells and theca cells) 25 Human Chorionic Gonadotrophin (hCG) 1° Oocyte meiosis resumption follicular rupture Ovulation triggering 2° promotes the maintenance of the corpus luteum during the beginning of pregnancy http://openlearn.open.ac.uk/mod/oucontent/view.php?id=398496§io n=1.3.5 Progesterone and estradiol secretions enriches the uterus with a thick lining of blood vessels 26 Drugs Containing hCG Urinary hCG PREGNYL® Recombinant hCG OVITRELLE ® (E.U)/ OVIDREL ® (US) PROFASI ® NOVAREL ® Two questions can be asked 27 1.Which drug to take as the reference product to compare? « The reference product must have a MA in the E.U and must be manufactured in the E.U » (Overall guideline on B.S) Pregnyl® and Ovitrelle ® OK 2.Comparison with the urinary form or the recombinant form? No specific information in the guidelines : consultation with EMA would be needed 28 Identity Card • MA : 02/02/2001 (Centralised Procedure) • 250µg of Choriogonadotropin alfa (6500 IU) • Subcutaneous administration • Manufacturing process: recombinant DNA technology Indications 1) Adult women undergoing superovulation prior to assisted reproductive techniques such as in vitro fertilisation (IVF) 2) Anovulatory or oligoovulatory women Posology One vial of Ovitrelle ® 24 to 48 H after the last administration of a follicle stimulating hormone (FSH), i.e. when optimal stimulation of follicular growth is achieved. 29 Patents 1° Method of production: (January 1993) “Recombinant heterodimeric human fertility hormones, and methods, cells, and vectors and DNA for the production thereof ” Invention claimed: « when both subunits are produced in the same cell, a hormone is expressed which is biologically active” 01/93 Patent filed 02/01 M.A 01/13 End of patent 02/16 End of CCP = entry of Biosimilars 30 Patents 2° hCG Formulation: “We have surprisingly found that it is possible to obtain liquid stabilised formulations” Invention claimed: liquid pharmaceutical composition containing hCG stabilised with a polyalcohol (mannitol) or a non-reducing sugar (sucrose) Simplifies the way of use (avoid the reconstitution of lyophilised powder) And allows auto-injections with pre-filled pens Problem : patent expiry = 2021 The patent has to be challenged! 31 Which Guidelines to rely on ? Overarching Guideline CHMP/437/04 (under revision) Quality BWP/49348/05 (Under revision) General Non-clinical / Clinical BMWP/42482/05 (under revision) Insulin Somatropin Epoetin FSH Hep GCSF IF alfa Specific IF beta Original Revised New Under revision Mo Ab No specific guidelines for our product 32 What studies to perform? REFERENCE BIOLOGICAL MEDICINAL PRODUCT (Ovitrelle®) N.B : « the same reference product must be used for all 3 parts of the dossier » SIMILAR BIOLOGICAL MEDICINAL PRODUCT 33 QUALITY STUDIES 34 Quality studies A full Quality dossier: CTD Module 3 + Comparability exercise Key point all along the dossier!! 35 Which process to use? HOST CELLS Procaryotic cell (e.g E. coli) Eucaryotic cell Our protein of interest is glycosylated : needs post-traductional modifications Yeast cell Mammalian cell Chinese Hamster Ovary We have a better chance to reach the reference API quality by using the same host cells 36 Process Organism naturally expressing the protein of interest Genes of interest Wild vector α unit gene β unit gene Expression vector hCG Genetically modified CHO expressing the protein of interest r-hCG 37 Structural comparison Main risk: Biosynthetic process Inherent diversity of structural heterogenicity Possible diversity in the glycosylation profile hCG : highly glycosylated protein GL: « given the complexity of the molecule and its inherent hetorogenecity, the set of analytical techniques should represent the state-of-the-art » 38 Structural comparison Example: Structural comparison of a marketed FSH (Gonal-f®) and its biosimilar Identical polypeptide chains But Different glycosylation pattern ( higher % of tri- and tetraantennary glycans) Glycosylation influences pharmacokinetics and may influence efficacy and safety 39 Example: Evaluation of BINOCRIT® (EPO biosimilar) compared to the reference EPREX® EPO = Glycoprotein : 165 amino acids 3 N-glycans 1 O-glycan EPAR: “Minor differences were observed at the glycosylation level but comparability was proved” GL:« Minor structural differences in the active substance, such as variability in post-translational modifications may be acceptable. » Depending on the Nonclinical and Clinical results 40 Impurities desired product ??? PROFILE Peptide variants Post-traductionnal variants degradation IMPURITY PROFILE Process and product- related impurities 41 Impurities Product-related impurities • oxydation • dissociated subunits • aggregates GL: « The product-related substances and impurities in the Biosimilar should be identified and compared to the reference product » Process-related impurities •residual DNA • host cell proteins and culture medium proteins • microbial/viral contaminations • bacterial endotoxins GL: « The process-related impurities are expected to differ from one to another process: their comparison may not be relevant » Non clinical and clinical studies to perform will be determined by the level of differences of impurities between the 2 products 42 REFERENCE BIOLOGICAL MEDICINAL PRODUCT (Ovitrelle®) SIMILAR BIOLOGICAL MEDICINAL PRODUCT 43 NON CLINICAL STUDIES 44 Pharmacodynamic studies a) In vitro bioassays To establish comparability in reactivity Tools: Primary granulosa cells Permanently cultured cells Advantages •LH/CG Receptor is investigated in its natural context • provides enough material Drawbacks • Limited number of cells • relies on artificial construct LH/CG-R MA-10 cells 45 Pharmacodynamic studies - Binding assays Expected results: MA-10 cell Binding constant Ovitrelle = Binding constant Biosimilar Ovitrelle® or Biosimilar - Potency Progesterone MA-10 cell Ovitrelle ® or Biosimilar Expected results: [Progesterone] with Ovitrelle = [Progesterone] with Biosimilar 46 Pharmacodynamic studies b) In vivo bioassays in vitro studies may not fully reflect the more complex situation in vivo additional comparative in vivo studies should be performed. Tests on adult female monkeys. For both products, we should see: • the production of oocytes of the same maturity • the same hormonal activities on luteinisation of ovarian follicles • identical time course of action 47 Toxicological studies Single dose toxicity – SC (rats and monkeys) No expected effects Repeat Dose toxicity – SC (rats and monkeys) Expected effects: • Hormonal disturbances (smaller testes, enlargement of the ovaries…) + search of antibodies to r-hCG GL:« Normally, other routine toxicological studies (safety pharmacology, reproduction toxicology, mutagenicity and carcinogenicity studies) are not required for biosimilars.» 48 REFERENCE BIOLOGICAL MEDICINAL PRODUCT (Ovitrelle®) SIMILAR BIOLOGICAL MEDICINAL PRODUCT 49 CLINICAL STUDIES 50 Clinical studies In accordance with Guideline on non-clinical and clinical development of similar biological medicinal products containing recombinant human follicle stimulating hormone (r-hFSH) & Guideline Similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues 51 Aim of these studies : Non inferiority and Non superiority ! 52 Pharmacokinetic studies Single dose, steady state or repeated determination of PK parameters : Administration SC : Single dose Ovitrelle ® : 250 µg BioS :250 µg Dosage : Radioimmunoassay 53 GL: “The pharmacokinetic parameters of interest are AUC, cmax, tmax, t1/2 and clearance. For the AUC and cmax, the 90% confidence interval of the ratio test/reference should lie within the acceptance range of 80% to 125%” AUC and Cmax absorption/bioavailability about 40 % differencies in elimination half life elimination = 30 h Accepted range 80-125% 54 Pharmacodynamic studies Biosimilar vs Reference in a revelant population in order to demonstrate therapeutic efficacy of the product : 12 healthy volunteers 6 female volunteers under oral contraceptive Ovarian supression Ovitrelle® 250 µg Biosimilar 250 µg 6 male volunteers previously pituitary down-regulated 55 Pharmacodynamic studies measuring androstenedione and testosterone exogenous administration after pituitary/ovarian downregulation is capable of initiating the aimed effect of stimulation of the testes/ovaries, as shown by the increase in testosterone GL: The pharmacodynamic (PD) markers should be selected on the basis of their relevance to demonstrate therapeutic efficacy of the product. The pharmacodynamic effect of the test and the reference medicinal products should be compared in a population where the possible differences can best be observed 56 If results are comparable to the Reference : Efficacy Trial If it’s not comparable to the Reference : Full Development with a complete dossier No biosimilar product If results tend to be comparable: Study PK/PD 57 PK/PD Best conclusion : PD effects produced by both Biosimilar and Reference are similar and this further supports PK bioequivalence 58 Efficacy trials Study Phase III: multicentre trials, double blind, randomised 200 FIV Primary parameter oocytes retrieved Secondary parameters oocyte maturity and quality, fertilisation, implantation and pregnancy GL: “Usually comparative clinical trials will be necessary to demonstrate clinical comparability between the similar biological and the reference medicinal product” 59 Efficacy trials Major inclusion criteria Major exclusion criteria Infertility Systemic disease 20-38 years old Polycistic ovarian syndrom Presence of both ovaries Previous OHSS No more than 3 previous assisted conception cycles Previous IVF failure Aim : 11 +/- 3 oocytes retrieved 60 If the biosimilar shows adequate comparability to the innovator product for one indication, it may be reasonable to extend the approval of the biosimilar to all the indications of the innovator product Ex : Omnitrope® Comparability studies between Omnitrope® and the reference product (Genotropin®) were conducted only in children with growth disturbances Omnitrope® including the indication for use in adults Reasons for the extrapolation : (1) the long clinical history of safe use of growth hormone; (2) the wide therapeutic window of the drug; (3) the rarity of reports of neutralizing antibodies; (4) the ability to characterize the structure and biological activity of growth hormones by physicochemical and biological methods (5) the variety of assays available to characterize the active and product-related substances 61 Clinical safety GL: Data from the efficacy trial will usually be sufficient to characterize the adverse event profile of the biosimilar product Monitoring adverse events during efficacy trials Focus on well-known adverse events like OHSS : Ovarian HyperStimulation Syndrom (2%) Symptoms : urination significantly darker, calf and chest pains, ascites… Symptoms generally resolve in 1 to 2 weeks, but will be more severe and persist longer if pregnancy occurs Complications:ovarian torsion, ovarian rupture, thrombophlebitis and renal insufficiency Treatment : aspiration ascites, electrolytes 62 Clinical safety - The most common side effects are: general disorders (headache, tiredness) gastro-intestinal system disorders (vomiting/nausea, abdominal pain) application site disorders (local reaction/pain at injection site) Uncommon side effects are: - psychiatric disorders (depression, irritability, restlessness) - gastrointestinal system disorders (diarrhoea) And … Measurements of antibodies before and after treatment (immunogenicity evaluation) Post-treatment visit (15-17 days after treatment) 63 Immunogenicity Ovitrelle® no immunogenicity demonstrated Biosimilar : Hyp 1: all patients tested for anti-hCG antibodies after a single dose were negative not immunogenic Hyp 2 : anti-hCG antibodies found immunogenicity Immunogenicity is more likely to occur when the therapeutic protein is given intermittently than continuously and the subcutaneous route of administration is more immunogenic than the intravenous one 64 REFERENCE BIOLOGICAL MEDICINAL PRODUCT (Ovitrelle®) SIMILAR BIOLOGICAL MEDICINAL PRODUCT 65 POST-MARKETING ACTIVITIES 66 Pharmacovigilance 2 safety issues to distinguish Product specific: linked to differences in the process Therapeutic class specific GL: “risk management plan or pharmacovigilance plan must be submitted, taking into account risks identified during product development and potential risks” Clinical trials were performed considering only one indication: safety must be certified for both GL: “it is important to consider the risk of immunogenicity in different therapeutic indications separately” 67 Risk management plan What to take into account: Refer to FSH Guideline: GL: “The risk management plan should include identified and potential risks associated with the use of r-hFSH containing medicinal products” Immunogenicity OHSS Critical points to be monitored 68 Global rules for Pharmacovigilance An adverse reaction report for any biological drug should always include : full name of the biological drug batch number Naming rules 69 Naming Overall GuideLine: « In order to support PharmacoVigilance monitoring, the specific medicinal product given to the patient should be clearly identified » “The name, appearance, and packaging of a biosimilar medicine should differ from those of the reference product “ One biosimilar = one brand name Licit, Distinctive & Available Only one submission in UE (OHMI) in class 5 10-15 proposed names 70 Naming 6 Proposed names to EMA: - Procreal® - Procrealine ® - Gonadoline ® - Fecondial ® - Fecondialine ® maximum 3 of them in accordance with NRG criteria & the GUIDELINE ON THE ACCEPTABILITY OF NAMES FOR HUMAN MEDICINAL PRODUCTS PROCESSED THROUGH THE CENTRALISED PROCEDURE - Chorial ® Waiting for authorities’ decisions Fecondialine® 71 PRICING ISSUES 72 How can we fix the cost of a biosimilar? 3 main points to consider: 1. Duration and cost of the development Up to 8 years and at least € 100 Millions Source: Lonza, Teva 73 How can we fix the cost of a biosimilar? As a comparison: Chemical generic drugs 1 – 10 € Millions Biosimilar > 100 € Millions… ... + Additionnal costs: • Institution of a Pharmacovigilance plan • Recruiting sales forces Convince skeptikal physicians that the Biosimilar is as « good » as the reference product. Ex : Gynaecologists for the Biosimilar of Ovitrelle® Fixed costs for Biosimilars are much higher than for chemical generic drugs ! 74 How can we fix the cost of a biosimilar? 2. Cost of manufacturing Huge investments in Biosimilars manufacturing processes compared to those for generic synthetic drugs 75 How can we fix the cost of a biosimilar? 3. Number of competitors on the market Limited number of Biosimilars manufacturers: Sandoz Teva… Vs. Large number of Generics manufacturers: Ex in France: (Biogaran, Alter, Arrow, EG, Mylan, Sandoz…) One year after the entry of the 1st Biosimilar/Generics manufacturer, it is estimated that there will be on the market: 2 Biosimilar manufacturers Vs. 9 Generic manufacturers 76 Entry and Competition in Generic Biologics (Henry G. Grabowski*, David B. Ridley and Kevin A. Schulman) How can we fix the cost of a biosimilar? Taking into consideration these 3 points: Discounts on Biosimilars will not be as high as for chemical Generics Maximum discounts observed in the E.U after 2 years of Marketing: Biosimilar Entry and Competition in Generic Biologics (Henry G. Grabowski*, David B. Ridley and Kevin A. Schulman) Chemical Generic 77 How can we fix the cost of a biosimilar? Example of Somatropin Biosimilar: = 36,11 € Targeted price for our Biosimilar = 28,50€ 78 Public health expenditures EMA estimation : BS generated annual savings of 1,4 billion euros in the E.U in 2009 NICE Decision in May 2010: Omnitrope : 1st Biosimilar recommended « When more than one product is suitable, the least costly option should be chosen » Cost difference Effectiveness difference Biosimilars should have their points on this axis 79 Ovitrelle® biosimilar: best choice? A.S Choriogonadotrophin alfa Administration Structure SC (auto-injections) Highly Glycosylated protein Follitropin alfa SC (auto-injections) Highly Glycosylated protein Same Quality concerns Number of ind. 2 4 (3 for women + 1 for men) Specific guidelines? NO YES Revenues in 2010 45 millions € 504 millions € 80 Conclusion At the end of the development, can we answer to our previous issues? How can the level of similarity be well established ? Comparability exercise Quality Safety Clinical efficacy-safety • How can the risks associated be defined ? Cannot be fully defined during Pre-authorisation development Importance of PV and MRP How similar is similar enough ? What about a full dossier? 81 Thanks for your attention! 82