Nanosimilars Beat Flühmann Global Lead NBCD Vifor Pharma Ltd Steering committe member of the NBCD Working Group NBCD A n increasingly important drug class 2 Nanosimilars ID: 1021985
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1. Challenges in Assessing Therapeutic Equivalence of NanosimilarsBeat FlühmannGlobal Lead NBCD Vifor Pharma LtdSteering committe member of the NBCD Working Group
2. NBCD:An increasingly important drug class2Nanosimilars+ 52 in clinical development24 parenteral nanomedicines on the marketOriginal NanomedicinesIron sucroseVenofer®19501990200020202010PEGylated liposomal doxorubicin hydrochlorideDoxil® / Cealyx®Glatiramer acetateCopaxone®Iron sucrose similarsGlatiramerLipodox®Albumin-Paclitaxel Abraxane®
3. Significant drop in mean Hb after switch from Venofer® to FerMylan®Mean Hb value 11.78±0.99 g/dL vs 11.48±0.98 g/dL (P1 vs P2; p=0.01)Rottembourg J et al. Nephrol Dial Transplant 2011
4. Significant increase in mean I.V. iron consumption after switch from Venofer® to FerMylan®34.6% increase in I.V. iron during P2 vs. P1 (p=0.001)12.6% increase in mean ESA dose P2 vs. P1Rottembourg J et al. Nephrol Dial Transplant 2011
5. Observed Clinical Differences→ Scientific Discussions5Martin-Malo A, et al. Nephrol Dial Transplant 2011; Stein J et al., Curr Med Res Opin 2012; Lee et al. Curr Med Res Opin 2013; Rottembourg J et al. Nephrol Dial Transplant 2011: Agüera ML et al. PLoS One. 2015 Aug 31;10(8):e0135967. doi: 10.1371/journal.pone.0135967; Hussaart et al. Ann. N.Y. Acad. Sci. xxxx (2017) 1–11 doi: 10.1111/nyas.13347
6. Non-Biological Complex Drugs (NBCD)6Crommelin DJ, de Vlieger JS, Weinstein V, Mühlebach S, Shah VP, Schellekens H. Different pharmaceutical products need similar terminology. The AAPS journal. 2014;16:11-14Synthetic, not a biologic, large molecular, non homomolecularThe entire complex is the active pharmaceutical ingredientThe properties cannot be fully characterized by physico-chemical analysisThe manufacturing process is fundamental to create the product and is difficult to controlABCExamples of complex drugsA iron carbohydratesB Liposomal drugsC Glatiramoids
7. Manufacturing defines the clinical profile of NanomedicinesUnknown critical quality attributes like size and morphology of the particles can influence the uptake and tissue distribution finally affecting the clinical outcomeAfter injection nano particles are absorbed and degraded by macrophages.
8. Distinct Physical Properties of Nanomedicines8Astier et al. Ann. N.Y. Acad. Sci. xxxx (2017) 1–11 doi: 10.1111/nyas.13382
9. Complex Landscape Hussaart et al. Ann. N.Y. Acad. Sci. xxxx (2017) 1–11 doi: 10.1111/nyas.13347
10. NBCD share many characteristics with biologicsBased on Schellekens et al; Regul Toxicol Pharmacol. 2011 Feb;59(1):176-83SMALL MOLECULE DRUGSMolecular weightLow (<500 Da)StructureWell definedManufacturingChemical synthesisCharacterizationComplete characterizationCopycharacteristicsIdentical copies can be madeBIOLOGICSNBCDsHigh (5-900 kDa)Complex, heterogeneous, defined by manufacturing processProduced in living cells or organismsSynthetic technologies (including nanotech)Not fully characterizedImpossible to ensure identical copy versions
11. Current regulatory PathwaysGenerics pathway Biosimilar pathway PE + BE = TEPK/PD + (pre-) clinical = highly similar Market accessMarket access
12. Current regulatory Pathwaysare not suitable for NBCD approvalGenerics pathway Biosimilar pathway PE + BE = TE Legislation prevents NBCD evaluation through the biosimilar pathway (because NBCDs are not biologicals)PK/PD + (pre-) clinical = highly similarMarket accessMarket access
13. Current regulatory Pathwaysare not suitable for NBCD approvalGenerics pathway Biosimilar pathway PE + BE = TE Legislation prevents NBCD evaluation through the biosimilar pathway (because NBCDs are not biologicals)PE + BE = TEPK/PD + (pre-) clinical = highly similarMarket accessMarket accessClinically meaningful critical quality attributes?
14. Critical quality attributes need to be clinically meaningful
15. Current regulatory Pathwaysare not suitable for NBCD approvalGenerics pathway Biosimilar pathway PE + BE = TE Legislation prevents NBCD evaluation through the biosimilar pathway (because NBCDs are not biologicals)PE + BE = TEIt is impossible to establish PE and BE for NBCDsPK/PD + (pre-) clinical = highly similarMarket accessMarket access
16. The similarity approach Based on Schellekens et al; Regul Toxicol Pharmacol. 2011 Feb;59(1):176-83.SMALL MOLECULE DRUGSCopycharacteristicsIdentical copies can be madeBIOLOGICSNBCDsImpossible to ensure identical copy versionsGENERICS APPROACHWell-established worldwideAuthorization of follow-on versionsPharmaceutical equivalence+ Bio-equivalence= Therapeutic equivalenceInterchangeableBIOSIMILAR APPROACHIn use and gaining tractionSIMILAR APPROACHBeing discusses and under developmentTotality of the evidenceHow similar?Therapeutic alternative?Interchangeable? Substitutable?
17. White Paper published with regulators17Hussaart et al. Ann. N.Y. Acad. Sci. xxxx (2017) 1–11 doi: 10.1111/nyas.13347Identified open challenges:Assessment of critical attributes to establish equivalence for follow-on versionsPublish scientific findings in the public domain to further progressNecessity to develop worldwide consensus for nomenclature and labeling Regulatory actions when substandard complex drug products are identified
18. Scientific Discussions Triggered Regulatory Actions 18Martin-Malo A, et al. Nephrol Dial Transplant 2011; Stein J et al., Curr Med Res Opin 2012; Lee et al. Curr Med Res Opin 2013; Rottembourg J et al. Nephrol Dial Transplant 2011: Agüera ML et al. PLoS One. 2015 Aug 31;10(8):e0135967. doi: 10.1371/journal.pone.0135967; Hussaart et al. Ann. N.Y. Acad. Sci. xxxx (2017) 1–11 doi: 10.1111/nyas.13347
19. Current Regulatory Requirements for ISS19Source:European Medicines Agency. Reflection paper on the data requirements for intravenous iron-based nano-colloidal products developed with reference to an innovator medicinal product. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2015/03/WC500184922.pdf Accessed 20.10.2015NBCD-Working group proposalFDAEMAPhysicochemical testsPharmacopoiaParticle size and distributionLabile ironMicroscopic methodsNon clinical biodistribution PK studyClinical PD studyRMPFDA. Draft Guidance for Industry on Bioequivalence Recommendations for Iron Sucrose Injectionhttp://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM297630.pdf. Accessed 2014.
20. GDUFA Regulatory Science Priorities 201720https://www.fda.gov/downloads/ForIndustry/UserFees/GenericDrugUserFees/UCM526900.pdf“Equivalence of complex drug products includes research into making generic versions available in all product categories, including complex drugs with unique characteristics. FDA spends an increasing amount of time reviewing and developing policy for complex drug products, and future generic products will need to demonstrate equivalence to increasingly complex RLDs. This scientific research supports the development of guidance and policy that clarifies the Abbreviated New Drug Application (ANDA) pathway for complex products, such as drug-device combinations, transdermal systems, implants and parenteral microspheres, nanomaterials (e.g. liposomes and iron colloids), and products that contain complex mixtures and peptides. Research continues into new guidance for transdermal irritation studies and for human factors studies that will aid in evaluation of product substitutability and robustness for drug-device combinations.” Post-market evaluation of generic drugs • Equivalence of complex products • Equivalence of locally-acting products • Therapeutic equivalence evaluation and standards • Computational and analytical tools
21. Pharmacists are not Aware of Differences Between Different Iron Sucrose Brands21Knoeff J, et al. Eur J Hosp Pharm 2017;0:1–6. doi:10.1136/ejhpharm-2016-001059Iron sucrose similars are just as effective as the originatorIron sucrose similars are just as safe as the originator
22. Pharmacists Substitute Iron Sucrose 22Knoeff J, et al. Eur J Hosp Pharm 2017;0:1–6. doi:10.1136/ejhpharm-2016-001059Dispensing ISS is decision of physician or in agreementDispensing ISS is decision of the pharmacistDispending ISS is a requirement
23. Need for guidance: Expert Round Table Vienna March 17th 2016Leading hospital pharmacists from Belgium; France; Germany; Spain; Switzerland; USAGoal: Reach consensus on how to select nanosimilars in hospital formularies and how to evaluate substitution and interchangeApproach: Identification of additional evaluation criteria relevant for nanosimilars based on selection criteria for biosimilars as starting pointDeliverable: Publication recommending a checklist of considerations for formulary selection 23
24. Manufacturing Defines the Product and the Clinical Outcome24Manufacturing processSize distribution Physical Characteristics Storage and handling:Temperature / light / package materialUncaptured pharmacological active moiety Physical stabilityParticle morphologyPK/Clinical outcome
25. Starting PointFormulary Selection Criteria for Biosimilars25Adapted from Griffith N, et al. Hospital Pharmacy 2014 Supply reliability History of drug shortages Supply chain security Anti-counterfeit measuresPatient assistance programsReimbursement support Manufacturer services, expertiseManufacturer considerationsProduct packaging and labeling Bar codingCompatibility with CSTDs*, robotics Ready-to-use preparation and administrationStability for ready-to-use administration Storage requirements Product considerations Economic considerations Hospital PayerPatientTransitions of careIT and medication system changesEducational requirements Pharmacovigilance requirements Hospital and patient factors Pharmacokinetics UptakeDistribution Clinical dataRange of indicationsImmunogenicityPotential for therapeutic interchange Number of similar agents on formulary Pharmacovigilance requirements Efficacy/Safety
26. OutcomeFormulary Selection Criteria for Nanosimilars26Adapted from Griffith N, et al. Hospital Pharmacy 2014 Supply reliability History of drug shortages Supply chain security Anti-counterfeit measuresPatient assistance programsReimbursement support Manufacturer services, expertiseProduct packaging and labeling Bar codingCompatibility with CSTDs*, robotics Ready-to-use preparation and administrationStability for ready-to-use administration Storage requirements Economic considerations Hospital PayerPatientTransitions of careIT and medication system changesEducational requirements Pharmacovigilance requirements Pharmacokinetics UptakeDistributiontrClinical dataRange of indicationsImmunogenicityPotential for therapeutic interchange Number of similar agents on formulary Pharmacovigilance requirements Chemical composition IdentityQuantityPharamacopoial specificationsParticle size and size distributionParticle surface characteristics Uncaptured pharmacological active moiety fractionStorage stability Pharmaceutical quality Manufacturer considerationsProduct considerations Hospital and patient factors Efficacy/Safety
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