Prof. Stefan Mühlebach, PhD
Transcript of Prof. Stefan Mühlebach, PhD
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
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1. Background 2. The similarity approach 3. Regulatory issues 4. Conclusions
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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
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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)
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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
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Mühlebach S, Vulto A, Weinstein V, Flühmann B, Shah V. GaBi J 2013;2(4):204-7
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1. Background 2. The similarity approach 3. Regulatory issues 4. Conclusions
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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)!
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• 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
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■ 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
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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)
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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?
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Regulatory challenges and approaches to characterize nanomedicines and their follow-on similars. Nanomedicine 2015;10(4), 659–674
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1. Background 2. The similarity approach 3. Regulatory issues 4. Conclusions
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• 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
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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
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■ 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]
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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
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1. Background 2. The similarity approach 3. Regulatory issues 4. Conclusions
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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?
?
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• 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
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§ 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’
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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’
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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.
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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
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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