Prof. Stefan Mühlebach, PhDrbbbd.com/Files/abf96463-81ff-4a3e-921f-b307c0072c97.pdf · 2015. 10. 27. · Iron sucrose similars non equivalence 4. Regulatory issues and conclusions

Sept 17, 2015

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

SM1 2015 Bioequivalence, Dissolution, Biosimilarity Conference (Antalya)

http://menaconf.com/index.php�

2nd MENA REGULATORY CONFERENCE AMMAN (JORDAN) Sept 15-17, 2015 Sept 17, 2015

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: http://www.acronymfinder.com/Non_Biological-Complex-Drug-(NBCD).html

http://www.tipharma.com/pharmaceutical-research-projects/regulatory-innovation/non-biological-complex-drugs-working-group.html



Composition and Structure Initiated in 2009 at the TI Pharma Workshop

‘Bioequivalence of Complex Drugs’*

Steering Committee

Expert panel

Working Group

Group of international experts from:

• Knowledge institutes o Academia o Medical Centers

• Industry • Various (e.g. ex-regulators)

Expert panel: open!

* Regul Toxicol Pharmacol 2011;59:176-183;8(50)973-977 (Therapeutic equivalence of complex drugs)



1. The sameness and the similarity approach

2. Non biological complex drugs 3. Iron sucrose similars non equivalence 4. Regulatory issues and conclusions



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

Clinical efficacy and Safety studies

not required

Generics interchangeable

substitutable

Therapeutically equivalent The generic paradigm is only applicable

to fully characterized active pharmaceutical ingredients (small molecules)!


2nd MENA REGULATORY CONFERENCE AMMAN (JORDAN) Sept 15-17, 2015 Sept 17, 2015 SM6

“Generic” (identical copy)

Small single molecule (ASA: 180 g/Mol)

=

Large, complex molecules (mix)

(Mol range EPO: 34-39 kD)

“Similar” (non- identical copy)

=



Small molecule drugs Biological drugs Size Small (single molecule)

Low molecular weight Large (mixture of related molecules) High molecular weight

Structure Simple, well defined, independent of manufacturing process

Complex (heterogeneous), defined by the exact manufacturing process

Modification Well defined Many options Manufacturing Produced by chemical synthesis

Predictable chemical process Identical copy can be made

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 2015. ISBN 978-3-319-16241-6)



Generic approach

Copy characteristics

Not fully characterized complex products (large molecules)

Therapeutic equivalence

(interchangeable)

Biosimilar approach (protein product)

Pharmaceutical equivalence

Pharmacological equivalence

(bioequivalence)

Fully identified and characterized

small molecule(s)

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 2015. ISBN 978-3-319-16241-6 (eBook) Adapted from Regul Toxicol Pharmacol 2011;59:176-183;8(50)973-977 (Therapeutic equivalence of complex drugs)

How similar? Totality of characteristics

Therap. alternative? Substitutable?

Interchangeable?



c

Mühlebach S. et al. 16th EAHP Congr. Vienna 2011, abstr. PHC030 (p.131)

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. Nanomedicine 2015;10(4):659-74



L = Liver S = Spleen BM = Bone marrow

Changes in the concentration of 52Fe in the tissue over time Transverse section Sagital section

0.5 h

6 h

L BM S L BM

Low High

52Fe Activity/Concentration

Beshara S et al. Br J Hematol 1999;104:296-302 (by permission from John Wiley and Sons)

RES = reticuoendothelial system



Terminology from Crommelin DJA et al. AAPS J 2014;16-14

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



Small molecules drugs (m.w.


Purification procedures Synthetic procedure (Isolation of core then addition of sucrose ligand; production

of core in the presence of ligand)

Starting materials (Iron source (e.g. FeCl3

or Fe2(SO4)3); Base (e.g. NaOH, Na2CO3 or NH3)

Concentrations of the reagents

pH of the reaction mixture at

different stages of the synthesis

Reaction temperature Reaction time

Terminal product manufacturing Adapted from Mühlebach S et al. Iron carbohydrate complexes, in: Adv in pharm.sci series no. 20, AAPSpress 2015



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



0 2 4 6 8

10 12 14 16 18 20

Per

cent

age/

area

*

ISS Test 1

*

ISS Test 2 Venofer **

Control

*Versus Venofer and control p


Toblli J et al. Biometals 2015;28(2):279-92

Isorigin 1 Isorigin.2

Isorigin.3



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;26:3262–3267



Eun Sil Lee ES et al. Curr Med Res Opin 2013;29:141-147



• 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




Follow-on versions of NBCDs:�Is there a harmonized regulatory approach?�Learning from the colloidal IV iron exampleTI Pharma NBCD working group (I)TI Pharma NBCD working group (II)LayoutTherapeutic equivalence of follow-on copies Biologic follow-ons(Complex Drugs): �Similar but not the same (comparable?)Characteristics: �Small molecule drugs vs. biologicalsHarmonized authorizations of follow-on versionsLayoutSlide Number 10i.v. iron nanoparticles / nanocolloidals:�Characteristics (iron sucrose example) PET scans confirm rapid uptake of iron �from iron sucrose originator by RESAssessing Ion Sucrose Similars (ISS): Comparability of follow-on versionsRegulatory approach for follow-on versions of (nano-)NBCDsi.v. iron carbohydrates: Parameters influencing the manufacturing processNBCD (nanoparticular) similars: Minor variations impacting safety & efficacyLayoutNonclinical: Iron deposits in rat liver �ISoriginator vs. ISSIsorig. vs ISS in nonanemic rats (40mg/kg/w)�Immunostaining (Ferritin), Prussian blue (Fe3+)Switching from IS Originator to an ISSauthorized �in stable HD patientsAdverse Drug Reaction: ISorig vs. ISS �(Obstetrics and Gynecology)LayoutHarmonized regulatory approach for �NBCD similiars?Slide Number 24

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Prof. Stefan Mühlebach, PhDrbbbd.com/Files/abf96463-81ff-4a3e-921f-b307c0072c97.pdf · 2015. 10. 27. · Iron sucrose similars non equivalence 4. Regulatory issues and conclusions