Prof. Stefan Mühlebach, PhD

Transcription

1 Prof. Stefan Mühlebach, PhD NBCD WG at TI Pharma, The Netherlands: Chair Vifor Pharma Ltd: Scientific Director GRA University of Basel: Prof. in Pharmacology & Hospital Pharmacy 2015 Bioequivalence, Dissolution, Biosimilarity Conference (Antalya) SM1

2 Declaration of Interest The NBCD WG hosted by TI Pharma addresses appropriate and aligned science-based approval and post-approval standards for NBCDs. The WG, consisting of experts from industry, academia and research institutes, disseminates its findings and engages in education and training programs. To guarantee that NBCDs and their follow-on products are safe and that they benefit patients, the NBCD WG actively works with all stakeholders to come to a consensus on how to deal with this important topic.. The founding industrial members of the NBCD WG are Teva Pharmaceutical Industries Ltd. Vifor Pharma Ltd, Sanofi and TI Pharma. Since 2015, Allergan is also supporting the activities of the WG. *NBCD is a defined acronym:

3 Composition and Structure Initiated in 2009 at the TI Pharma Workshop Bioequivalence of Complex Drugs * Steering Committee Expert panel Expert panel: open! Working Group Group of international experts from: Knowledge institutes o Academia o Medical Centers Industry Various (e.g. ex-regulators) * Regul Toxicol Pharmacol 2011;59: ;8(50) (Therapeutic equivalence of complex drugs)

4 1. The sameness and the similarity approach 2. Non biological complex drugs 3. Iron sucrose similars non equivalence 4. Regulatory issues and conclusions

5 Generic paradigm for conventional drugs (EMA, FDA): Pharmaceutically equivalent (identical API/formulation): the same Bioequivalent in healthy subjects (volunteers): comparable AUC comparable PK / PD / safety Generics interchangeable substitutable Clinical efficacy and Safety studies not required Therapeutically equivalent The generic paradigm is only applicable to fully characterized active pharmaceutical ingredients (small molecules)!

6 = Small single molecule (ASA: 180 g/mol) Generic (identical copy) = Large, complex molecules (mix) (Mol range EPO: kd) Similar (non- identical copy) SM6

7 Size Structure Small molecule drugs Small (single molecule) Low molecular weight Simple, well defined, independent of manufacturing process Modification Well defined Many options Manufacturing Produced by chemical synthesis Predictable chemical process Identical copy can be made Biological drugs Large (mixture of related molecules) High molecular weight Complex (heterogeneous), defined by the exact manufacturing process Produced in living cell culture Difficult to control from starting material to final Active Pharmaceutical Ingredient Impossible to ensure identical copy Characterization Easy to characterize completely Cannot be characterized completely the molecular composition and heterogenicity Stability Stable Unstable, sensitive to external conditions Immunogenicity Mostly non-immunogenic Immunogenic From Schellekens et al. Poster #R6341 AAPS/FIP (2010), Declerck GaBI J). 2012;1(1):13-6. In:NBCDs. The Science and Regulatory Landscape..Crommelin DJA, de Vlieger JSB (eds.).aaps ISBN ) SM7

8 Copy characteristics Fully identified and characterized small molecule(s) Not fully characterized complex products (large molecules) Generic approach Biosimilar approach (protein product) Pharmaceutical equivalence Therapeutic equivalence (interchangeable) Pharmacological equivalence (bioequivalence) How similar? Totality of characteristics Therap. alternative? Substitutable? Interchangeable? From: Non-Biological Complex Drugs. The Science and Regulatory Landscape..Crommelin DJA, de Vlieger JSB (eds.). AAPS Advances in the Pharmaceutical Sciences series vol.20. Springer publisher ISBN (ebook) Adapted from Regul Toxicol Pharmacol 2011;59: ;8(50) (Therapeutic equivalence of complex drugs)

9 1. The sameness and the similarity approach 2. Non biological complex drugs 3. Iron sucrose similars non equivalence 4. Regulatory issues and conclusions

10 Synthetic, not biological MP Not homo-molecular, closely related, often nanoparticular, polymeric structures Can t be fully characterized by physicochemical analytical means Unknown structural elements that might impact the therapeutic performance (clinically meaningful differences in copies?) The properties of the product dependent on the multi-step manufacturing process influencing composition, quality and in vivo performance From Crommelin DJA et al. AAPS J 2014;16-14 (Terminology) Mühlebach S. et al. 16th EAHP Congr. Vienna 2011, abstr. PHC030 (p.131) c

11 Mühlebach S. et al. Nanomedicine 2015;10(4): SM11

12 Changes in the concentration of 52 Fe in the tissue over time Transverse section Sagital section 0.5 h L BM S L BM L = Liver S = Spleen BM = Bone marrow 6 h Low High 52 Fe Activity/Concentration RES = reticuoendothelial system Beshara S et al. Br J Hematol 1999;104: (by permission from John Wiley and Sons) SM12

13 Synthetic, not biological medicinal products Not homo-molecular, closely related, nanoparticular, polymeric structures Can t be fully characterized by physicochemical analytical means Unknown structural elements might impact the therapeutic performance (clinically meaningful differences in copies?) The properties of the product dependent on the multi-step manufacturing process influencing composition, quality and in vivo performance Terminology from Crommelin DJA et al. AAPS J 2014;16-14 SM13

14 Generic approach? Biosimilar approach Small molecules drugs (m.w. <500) e.g., ASA Fully characterized Complex (non-biological) drugs (m.range 43[IS]-150kDa) e.g., polynuclear ferric hydroxide carbohydrate complexes, glatiramoids, liposomes Not fully characterized Complex (biological) drugs (m.range 5-150kDa) e.g., EPO Not fully characterized Nanomedicines addressing the scientific and regulatory gap. Ann N.Y.Acad Sci 2014 Apr;1313:35-56 SM14

15 Concentrations of the reagents Synthetic procedure (Isolation of core then addition of sucrose ligand; production of core in the presence of ligand) Starting materials (Iron source (e.g. FeCl 3 or Fe 2 (SO 4 ) 3 ); Base (e.g. NaOH, Na 2 CO 3 or NH 3 ) Purification procedures ph of the reaction mixture at different stages of the synthesis Reaction time Reaction temperature Terminal product manufacturing Adapted from Mühlebach S et al. Iron carbohydrate complexes, in: Adv in pharm.sci series no. 20, AAPSpress 2015 SM15

16 Mühlebach S, et al.gabi J 2013;2(4):204-7

17 1. The sameness and the similarity approach 2. Non biological complex drugs 3. Iron sucrose similars non equivalence 4. Regulatory issues and conclusions

18 ISS1 Significant iron deposits in the ISS Test 1 & ISS Test 2 groups may indicate reduced stability of the ISS complex. ISS more likely to induce oxidative stress than Venofer 1 40 randomised rats received weekly 40mg IV iron/kg for 4w Prussian blue staining Venofer ISS2 Percentage/area * ISS Test 1 * ISS Test 2 Venofer ** Control Control *Versus Venofer and control p<0.01 **Versus all groups p<0.01 Adapted from Toblli JE et al. Drug Research 2009; 59(4): SM18

19 Is origin 1 Is origin. 2 Is origin. 3 Toblli J et al. Biometals 2015;28(2): SM19

20 34.6% increase in IV iron during P2 vs. P1 12.6% increase in mean ESA dose P2 vs. P1 Adapted from Rottembourg et al. Nephrol Dial Transplant 2011;26: SM20

21 Eun Sil Lee ES et al. Curr Med Res Opin 2013;29: SM21

22 1. The sameness and the similarity approach 2. Non biological complex drugs 3. Iron sucrose similars non equivalence 4. Regulatory issues and conclusions

23 Alignment of regulatory views worldwide (terms, definition, harmonization) Comparability issues and product drift (how similar is similar enough?) How to deal with: Extrapolation? Interchangeability? Substitution? Naming, labelling? Crommelin DJA et al. AAPS J 2014;16 (1):11-14 (terninology) Schellekens H et al. AAPS J 2014;16(1):15-21 (points to consider) Slide adopted with courtesy from J. de Vlieger, NBCD working group SM23

24