June 20, 2014

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  

SM2 April 25, 2015

1.  Background 2.  The similarity approach 3.  Regulatory issues 4.  Conclusions

SM3 April 25, 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 NBCD WG was founded in 2009 by Teva Pharmaceutical Industries Ltd. Vifor Pharma Ltd, Sanofi and TI Pharma.

*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

SM4 April 25, 2015

NON BIOLOGICAL COMPLEX DRUGS are different than typical small molecule pharmaceutical agents

§  NBCDs are complex drugs comprised of large high molecular weight polymerics often with nanoparticular structures

§  The entire complex is the active pharmaceutical ingredient

§  The properties cannot be fully characterized by physicochemical analysis

§  The manufacturing process is fundamental to creating the correct and originator product

c  

Mühlebach S. et al. EAHP Vienna PHC030 (2011)

SM5 April 25, 2015

The percentage of cells with ROS production and apoptotic cells was significantly increased with ISS compared to Venofer at the end of the HD session

* *

* p< 0.005 ISS vs Venofer®

Alejandro Martin-Malo, et al. Nephrol Dial Transplant 2011

SM6 April 25, 2015

Mühlebach S, Vulto A, Weinstein V, Flühmann B, Shah V. GaBi J 2013;2(4):204-7

SM7 April 25, 2015

1.  Background 2.  The similarity approach 3.  Regulatory issues 4.  Conclusions

SM8 April 25, 2015

Generic paradigm for conventional drugs (EMA, FDA): ü Pharmaceutically equivalent (identical API/formulation): the same üBioequivalent 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)!

SM9 April 25, 2015

•  Three-dimensional, multicomponent (nanoparticular) structures (preferred spatial arrangement for functions).

•  Size (distribution), morphology and surface affect PK and PD: selective targeting of sites in the body and overcome barriers [structure modification (pro-drugs),active/passive transport, T½]; ….analytical tools?

•  Interactions with the innate immune system [mononuclear phagocytic system (RES)]: ADME (FPE), toxicity, efficacy …lacking in vivo models.

•  Endogenous compounds, central compartment? (BA, BE: AUC, cmax, PD biomarkers, dose range).

Desai N. AAPS J 2012;14(2):282-95: Challenges in development of nanoparticle-based therapeutics Cook CS J Bioequiv Availab 2011 (S1):1-5. Current issues on bioavailability and bioequivalence determination

SM10 April 25, 2015

￭  Nanomedicines are Medicinal Products [MP] using nanomaterials and nanotechnology during their development and manufacturing (size-specific design and manufacturing at an atomic or molecular level not to be accomplished at larger scales):

￭  Potential to revolutionize medicine but also safety concerns

Hoet P et al. Drug Safety. 2009;32(8), 625-636. Trinkle S et al. Ann. N.Y. Acad. Sci. 2014;313:35–56 Mühlebachj S et al, Nanomedicine 2015;10(4), 659–674

SM11 April 25, 2015

Small molecules drugs (m.w. <500) e.g., ASA

Fully characterized

Generic paradigm

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

Biosimilar approach

Ann N.Y.Acad Sci 2014 2014;313:35-56 (Nanomedicines addressing the scientific and regulatory gap)

SM12 April 25, 2015

Generic  approach  

Copy  characteris0cs  

Not  fully  characterized  

complex  product  (large  molecules)  

Therapeu,c  equivalence  

(interchangeable)    

Biosimilar  approach    (protein  product)  

Pharmaceu0cal  equivalence  

Pharmacological  equivalence  

(bioequivalence)  

Fully  iden,fied  and  characterized    

small  molecule(s)  

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

How  much  similar?  Totality  of  characteris0cs  

Therap.  alterna0ve?  Subs0tutable?  

Interchangeable?  

SM13 April 25, 2015

Regulatory challenges and approaches to characterize nanomedicines and their follow-on similars. Nanomedicine 2015;10(4), 659–674

SM14 April 25, 2015

1.  Background 2.  The similarity approach 3.  Regulatory issues 4.  Conclusions

SM15 April 25, 2015

•  Quality assessment (pharmacopoeia)

•  Reflection Papers, Industry guidance, educational sessions (Authorities)

WG of non-biological complexes

Revision iron sucrose injection monograph

Modernization of iron sucrose colloidal solution monograph

2015

SM16 April 25, 2015

BE recomm. Ferumoxytol

injection

TE evaluation IV iron

gluconate (Ferrlicit vs.

Nulecit)

2011 2013 2013

EMA

(2011-2015)

FDA

(2011-2013)

2011 2012 2013

Draft Guidance for Industry on BE for IS

Revised Draft Guidance on BE for Iron Sucrose

2013

2015

SM17 April 25, 2015

￭  Highly similar Pharmaceutical Quality (MP and stability) •  Structure, composition (CH) •  iron core (size, labile iron, polymorphism, morphology) •  Particle sizing, surface , charge •  Degradation, in-use stability

￭  Non-clinical (biodistribution) • Plasma • RES, “handling” • Target tissues (pharmacol., toxicol.) Methods: histology, MRI, MS, non-compartmental analysis, species variability, validation

￭  Clinical characterisation (PK (single dose, cross-over) → efficacy, safety)

• Biomarkers (ferrtint, Tsat, Hb,iron and EPO dose) • Safety (hypersensitivity, NTBI, AE, oxidat. stress) Methods: analytics

￭  PMS, RMP (concerns: hypersensitivity, Fe overload)

Weight of evidence approach for similarity (justifications!) [Reflection paper to assist to generate relevant data (quality, non-clinical and clinical) also for control of the manufacturing]

SM18 April 25, 2015

 

 Quality

Pharmaceutical comparability

Non-clinical

Clinical

http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2013/09/WC500149496.pdf

Based  on  current  scien,fic  and  regulatory  knowledge  /  experience  

SM19 April 25, 2015

1.  Background  2.  The  similarity  approach  3.  Regulatory  issues  4.  Conclusions  

SM20 April 25, 2015

Generic approach

Copy characteristics

Not fully characterized complex product (large molecules)

Therapeutic equivalence

(interchangeable)

Biosimilar approach (protein product)

Pharmaceutical equivalence

Bio- equivalence

Fully identified and characterized

small molecule(s)

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

How similar? Totality of evidence

Therapeutic alternative? Substitutable?

Interchangeable?

?

20

SM21 April 25, 2015

•  The new class of NBCDs and their follow-on versions need a new and not yet fully defined regulatory approach considering drug specific characteristics:

stepwise comparability/similarity approach: quality → (non ) clinical → head to head

•  Therapeutic equivalence to a RLD is challenged:

interchangeability of complex drugs (including NBCDs) needs to be shown in clinical studies.

Schellekens et al. AAPS J 2014;16_15-21. How to regulate NBCDs and their follow on versions: points to consider

SM22 April 25, 2015

§  Meeting Report SRACD Budapest 2014: The similarity question for biologicals and non-biological complex drugs. Eur. Journal of Pharmaceutical Sciences (EJPS: accepted for publication 2015)

§  Educational publications GaBiJ, educational series on NBCDs see 2014;3(2)

§  AAPS e-book in print Advances in the Pharmaceutical Sciences: ‘NBCDs: the science and the regulatory landscape’

SM23 April 25, 2015

SM24 April 25, 2015

Composi0on  and  Structure  

Steering  Committee

Expert  panel

Working  Group

Group  of  interna0onal  experts  from:  

•   Knowledge  ins,tutes  •   Academia  •   Medical  Centers  

•   Industry  

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

Expert  panel:  open!    

Ini,ated  in  2009  at  TI  Pharma  Workshop  ‘Bioequivalence  of  Complex  Drugs’  

SM25 April 25, 2015

2013: Nanomedicines: Addressing the Scientific and Regulatory Gap

www.nyas.org/NanoMed-eB

Sally Tinkle1, et al. online: 27 MAR 2014, DOI: 10.1111/nyas.12403

http://www.genengnews.com/insight-and-intelligence/nanotechnology-is-the-magic-bullet-becoming-reality/77900016/?kwrd=nanomedicines

REGULATORY CHALLENGES •  Unveiling the properties of nanomaterials and understanding the relevance of

those properties to the regulatory status of the specific products. •  The concept of generic substitution appears to open uncharted territory

when applied to nanomedicine. •  Non-biological complex drugs …presence of multiple different large

molecular structures, some of which may be nanoparticulate.

SM26 April 25, 2015

Ehmann  F  et  al.  Nanomedicine  2013;8(5):849-­‐856  

Surface properties/coatings: the importance for safety & efficacy. How to evaluate the ‘follow-on’ nanomedicine products, after 1st gen. products off patent. Nanoscience advances : creation of even more complex, hybrid structures. Examples: IV liposomal products, nanosized colloidal iron‑based preparations, block copolymer micelles

SM27 April 25, 2015

               TE  evalua0on  of  Nulecit™  vs.  Ferrlecit™  in  a  three-­‐year  project  

NTBI    forma0on  and  comparison  in  vivo:  oxida,ve  stress,  inflamma,on?  •     Physicochemical  characteriza0on  incl.  labile  iron  •     In  vivo  uptake,  labile  iron  leakage  compared  to  RLD:  

-­‐    Phagocytosis  assay  (RES  uptake)    -­‐    Prospec,ve,  well-­‐controlled  studies  on  Fe  distribu0on  in  ,ssue            species  (non-­‐clinical)  -­‐    Compare  NTBI  levels  in  hemodialysis  pa,ents  (cross-­‐over)  

Ra,onal:  EMA  2011  reflec,on  paper:    •  Plasma  levels  alone  of  limited  value  • Organ  or  ,ssue  Fe  distribu,on  from  non-­‐clinical  studies  to  support