Covance Comparability Studies: The Key to a Biosimilar's Success 
 

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Biosimilars, which are new versions of innovator biopharmaceutical products that are marketed after expiration of patents, have emerged as one of the fastest growing development opportunities in the ...

Biosimilars, which are new versions of innovator biopharmaceutical products that are marketed after expiration of patents, have emerged as one of the fastest growing development opportunities in the biopharmaceutical sector. In the U.S. alone, industry analysts estimate that biologics worth $80 billion are slated to go off patent by 2015.

Regulatory agencies evaluate biosimilars based on their level of similarity to, rather than the exact replication of, the innovator drug. In the U.S., recent guidance by the FDA says it will “consider the totality of the evidence” when assessing follow-on products. This approach requires sponsors to demonstrate robust chemical comparability to the innovator compound.

The need for increased analytics and the desire for compressed timelines in biosimilars development demands in particular that developers must invest early in Chemistry, Manufacturing, and Controls (CMC)-type analysis to demonstrate comparability to the reference molecule at every stage, particularly during manufacturing.

Due to the complexity of biologics, a product can only be made that is similar to the innovator drug, not identical. Basically, it’s impossible for two different manufacturers to produce two identical products even identical host expression systems, processes, and equivalent technologies are used. Therefore, we have to rely on analytics to compare the biosimilar to the innovator product on the market.

Read more at http://blog.covance.com/2013/03/key-to-biosimilars-success/

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  • This slide is to expand on the point that navigating the regulatory landscape could be a challenge. EMA established pathway for biosimilars in 2003. There have been numerous subsequent guidance documents. (Abbreviated approval pathway for Biosimilars created via the Patient Protection and Affordable Care Act. Signed on March 23, 2010. There was also a CRS report for Congress (FDA on follow on Biologics) issued in April 2010. Additionally, the FDA issued three draft guidance documents for biosimilar development in February 2012. Health Canada (Guidance on Subsequent Entry Biologics published in March 2010.) Japan (Guideline on quality, safety, and efficacy of follow-on biologics was published in March 2009) WHO (Guideline document on Evaluation of Similar Biotherapeutics Products adopted in October 2009) Detailed reg info re EMA and FDA available in the appendix If you know where the client is releasing their product, you can use region-specific slides. This is the point where you can ask if the client has set up a meeting with the regulatory agency. If they are not sure about how to do this, bring a Covance regulatory expert with you to the next meeting with the client.
  • Because of the complex science involved, the Regulators have indicated that the generic drug approval pathway is not appropriate for complex biologics. The “similar biological medicinal products” approach, based on a comparability exercise, will then have to be followed. In 2004, European Medicines Agency (EMEA) became the first regulatory body to issue guidance for the approval of biosimilars and there are several approved biosimilars in the EU The European Medicines Agency (EMA) is a decentralised agency of the European Union, located in London. The Agency is responsible for the scientific evaluation of medicines developed by pharmaceutical companies for use in the European Union.
  • Japan has guideline (in Japanese) and has approved a biosimilar The FDA in February 2012 provided 3 draft guidance documents that provide the FDA’s current thinking on key scientific and regulatory factors involved in submitting applications for biosimilar products to the agency. FDA is seeking public comment on these draft guidance documents: Scientific Considerations in Demonstrating Biosimilarity to a Reference Product: The draft guidance is intended to assist companies in demonstrating that a proposed therapeutic protein product is biosimilar to a reference product for the purpose of submitting an application, called a “351(k)” application, to the FDA. This draft guidance describes a risk-based “totality-of-the-evidence” approach that the FDA intends to use to evaluate the data and information submitted in support of a determination of biosimilarity of the proposed product to the reference product. As outlined in the draft guidance, FDA recommends a stepwise approach in the development of biosimilar products. Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product: The draft guidance provides an overview of analytical factors to consider when assessing biosimilarity between a proposed therapeutic protein product and a reference product for the purpose of submitting a 351(k) application. This includes the importance of extensive analytical, physico-chemical and biological characterization in demonstrating that the proposed biosimilar product is highly similar to the reference product notwithstanding minor differences in clinically inactive components. Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009: The draft guidance provides answers to common questions from people interested in developing biosimilar products. The question and answer format addresses questions that may arise in the early stages of product development, such as how to request meetings with the FDA, addressing differences in formulation from the reference product, how to request exclusivity, and other topics. 
  • Japan has guideline (in Japanese) and has approved a biosimilar The FDA in February 2012 provided 3 draft guidance documents that provide the FDA’s current thinking on key scientific and regulatory factors involved in submitting applications for biosimilar products to the agency. FDA is seeking public comment on these draft guidance documents: Scientific Considerations in Demonstrating Biosimilarity to a Reference Product: The draft guidance is intended to assist companies in demonstrating that a proposed therapeutic protein product is biosimilar to a reference product for the purpose of submitting an application, called a “351(k)” application, to the FDA. This draft guidance describes a risk-based “totality-of-the-evidence” approach that the FDA intends to use to evaluate the data and information submitted in support of a determination of biosimilarity of the proposed product to the reference product. As outlined in the draft guidance, FDA recommends a stepwise approach in the development of biosimilar products. Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product: The draft guidance provides an overview of analytical factors to consider when assessing biosimilarity between a proposed therapeutic protein product and a reference product for the purpose of submitting a 351(k) application. This includes the importance of extensive analytical, physico-chemical and biological characterization in demonstrating that the proposed biosimilar product is highly similar to the reference product notwithstanding minor differences in clinically inactive components. Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009: The draft guidance provides answers to common questions from people interested in developing biosimilar products. The question and answer format addresses questions that may arise in the early stages of product development, such as how to request meetings with the FDA, addressing differences in formulation from the reference product, how to request exclusivity, and other topics. 
  • This is to show what may need to be done in order to demonstrate “comparability” to the regulatory agencies. When presenting this slide, you can touch on “and Covance can do all these. We’ll get to that in a minute”.
  • If you know in which areas the client needs help with before giving this presentation, pick relevant slides from the “regulatory” and “development challenges” modules in the backup section to follow this slide during the presentation. This is the shorter version. If you feel the client needs some education on what it takes to develop a biosimilar, you can pick at least one separate slide to cover each major point stated here. This is the longer version. If you don’t know where the client needs help yet, you can ask them in which areas they need help using this slide or use individual slides in the longer version, depending on how much time you have with the client and their expertise on biosimilar development.
  • See appendix for details
  • The goal of this slide is to demonstrate we have biosimilar development capabilities through the continuum. We may not have done biosimilar work in everything listed here but we certainly have done biological work in all of them.

Covance Comparability Studies: The Key to a Biosimilar's Success  Presentation Transcript

  • 1. Comparability Studies:The Key to a Biosimilars Success Raymond Kaiser, PhD Global Vice President BioPharmaceutical CMC Solutions Covance
  • 2. Presentation OutlineWhat is “Biosimilarity”Global Regulatory CMC ExpectationsComparability ExpectationsAnalytical Approaches to Comparability“Real World” ObservationsQ&A2
  • 3. What is a Biosimilar?Biosimilars are follow-on biologics  New versions of innovator biopharmaceutical products, following patent expiryThe very nature of a biologic means  It is practically impossible for two different manufacturers to produce two identical biopharmaceuticals if identical host expression systems, processes and equivalent technologies are not used  This has to be demonstrated in an extensive comparability program3
  • 4. Biosimilar or Biosimilarity means:The biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive componentsThere are no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity, and potency of the product4
  • 5. Global Regulatory Landscape EMA (The European Medicines Agency) Established EMA approval pathway: 14 biosimilars approved* within the product classes of:  human growth hormone  granulocyte colony-stimulating factor (G-CSF)  erythropoietin US FDA Biologics Price and Innovation Act passed in 2010  Empowers FDA to develop standards to evaluate and approve biosimilars FDA February 2012 draft guidance documents  Risk-based “totality-of-the-evidence” approach Health Canada Guidance came out in 2010 Japan Guideline came out in 2009 WHO Guideline document came out in 2009 ROW Argentina,Australia (amending), Brazil, Jordan, Korea, Malaysia, Saudi Arabia, Singapore, Taiwan, Turkey, Venezuela – Guidelines available Colombia, Cuba, India, Mexico, South Africa, and Thailand – Draft Guidelines available Biosimilar Regulatory Guidance documents and discussions are on-going and expanding globally.5
  • 6. Regulatory Environment - EU Established EMA approval pathway  14 biosimilars approved within the product classes of:  Human growth hormone  Granulocyte colony-stimulating factor (G-CSF)  Erythropoietin Key EMA guidance documents  “Overarching” guideline on similar biological medicinal products  From 2005, currently being updated  Guideline on similar biological medicinal products containing biotechnology- derived proteins as active substances: quality issues  From 2005  Guideline on similar biological medicinal products containing biotechnology- derived proteins as active substances: nonclinical and clinical issues  From 2005, currently being updated to incorporate risk-related approaches6
  • 7. Regulatory Environment – US FDA approval pathway established Biologics Price and Innovation Act passed in 2010 empowers FDA to develop standards to evaluate and approve biosimilars FDA February 2012 draft guidance documents  Scientific Considerations in Demonstrating Biosimilarity to a Reference Product - Risk-based “totality-of-the-evidence” approach  Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product - Overview of analytical factors to consider, includes analytical, physico- chemical and biological characterization  Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009 - Provides answers to common questions that may arise in the early stages of product development7
  • 8. General Requirements of FDA Guidance A 351(k) application must include information demonstrating biosimilarity based on data derived from:  Analytical studies demonstrating that the biological product is “highly similar” to the reference product notwithstanding minor differences in clinically inactive components  Animal studies (including the assessment of toxicity)  A clinical study or studies (including the assessment of immunogenicity and pharmacokinetics (PK) or pharmacodynamics (PD)) that are sufficient to demonstrate safety, purity, and potency in 1 or more appropriate conditions of use for which the reference product is licensed FDA may determine, at its discretion, that an element described above is unnecessary in a 351(k) application8
  • 9. Regulatory Environment - ICH Regions How do the requirements compare?  US, EU and Japan all require comparability with reference product  Reference product must be registered under the Regulatory jurisdiction  In EU this is law  FDA will consider non-US registered reference product with studies to bridge to US reference  Japan requires Japanese registered product  Early engagement with Regulatory Authority is vital  Extrapolation of indications will be considered  At least one Phase III comparable efficacy study (usually with equivalence design) is required for licence9
  • 10. Regulatory Comparability Package Extensive Analytical & In Vitro  Extensive analytical characterization versus reference product(s)  If mAb  specificity & affinity to epitope  potency using CDC, ADCC &/or functional in vitro cell-based assays Limited in vivo Nonclinical  PK/PD studies, Toxicology (SD/MD), and Immunogenicity studies (requirement for nonhuman primates?) Limited Clinical  Phase I  comparability of PK/PD & Immunogenicity in volunteers or patients at reference dose and regimen for targeted indications  Phase III  comparability for safety and efficacy (single pivotal) based on PK/PD, surrogate endpoints and clinical outcomes Extensive Post-Approval  REMS and pharmacovigilance planning including patient registry(ies) for assessment of incidence of specific safety issues10
  • 11. Development Challenges Regulatory, manufacturing and marketing complexities Biosimilar must be highly similar to innovator biologic, which can be difficult to demonstrate as all data for innovator will be lacking A comparability exercise has to be followed with the innovator product at all levels of product development  Physico-chemical characterization  Biological activity  Preclinical in vivo comparability  Phase I PK and safety  Phase III efficacy and safety It’s all about comparability11
  • 12. Biosimilarity? How close do the proposed biosimilar products (figures B- E) compare to the reference product (figure A)? Advances in current state-of- the-art analytical methods enhance the likelihood that a product will be highly similar to another product by better targeting the original products physicochemical and functional properties‘Biosimilar Biological Product’ Webinar, Rachel Sherman, FDA, 15FEB201212
  • 13. FDA View‘Biosimilar Biological Product’ Webinar, Rachel Sherman, FDA, 15FEB201213
  • 14. Biosimilars must be Systematically Engineeredto Match the Reference ProductMark McCamish, Novartis, International Conference on Drug Development, Austin TX,29FEB201214
  • 15. CharacterizationComprehensive Characterization  Physicochemical as well as biological  Multiple batches from innovator spanning a number of years  Understand innovator variability  Specification changes over life of product  No label change15
  • 16. Biosimilars at Covance Year on year doubling of analytical demand for Biosimilars since 2008 Upgraded Protein Chemistry techniques with additional characterization to demonstrate comparability or understand differences Moved toward higher defining analytics (e.g. UPLC, LC/MS) Compounds 1000 500 250 100 20 1 DISCOVER DRUG DEVELOPMENT COMMERCIALIZATIO Y N Research Preclinical Phase I Phase II Ph. IIIa IIb Phase IV IND/CTA NDA /BLA Approval Biosimilarnuo mAcar a h C NBE 16
  • 17. Why More Characterization for Biosimilars?Client has to show high ‘similarity’ to Innovator “Proving ‘highly similar’ to the reference product often required multiple iterations of process change and physiochemical characterization” Characterization of the Innovator (beware literature!) Characterization of the Biosimilar Monitor Manufacture ‘Process is the product’ Monitor changes in Innovator Analytical tools for characterizing biopharmaceuticals and the implications for Biosimilars. S Berkowitz, J Mazzeo, G Jones, Nature review Vol 11, Jul 201217
  • 18. Why More Characterization for Biosimilars?18
  • 19. Protein Heterogeneity Amino Acid Substitution  Oxidation AA Misincorporation (e.g.  Carbamylation MET⇒NLE)  Carboxylation N- and C-terminal mods  Formylation Mismatched S-S bonds  γ-Carboxyglutamylation Folding  O-linked Glycosylation Truncation  N-linked Glycosylation Aggregation  Methylation Multimer Dissociation  Phosporylation Denaturation  Sulphation Acetylation  PEGylation Fatty acid acylation  etc. Deamidation19
  • 20. Analytical Tools to Evaluate Protein Structure (subset)Protein Functionality Analytical TechniqueAA Sequence and Mass Spectrometry (MS), peptide mapping, Edman SequenceModifications analysis, chromatographic separations S-S bonding, calorimetry, HDX and Ion mobility MS, NMR, CD,Folding FT & Raman spectroscopy, fluorescence, chromatographySubunit Interactions Chromatography, ion mobility MSHeterogeneity of size, Chromatography, gel & capillary electrophoresis, light scattercharge, hydrophobicityGlycosylation Anion exchange, enzymatic digestion, peptide mapping, CE, MSPEGylation & isomers Chromatography, peptide mappingBioactivity, cellular and Ligand & receptor binding (ELISA, SPR), signal transductionanimal bioassays Analytical ultracentrifugation, size-exclusion chromatography,Aggregation field flow fractionation, light scatter, microscopyProteolysis Electrophoresis, chromatography, MSImpurities Chromatography, proteomics, immunoassays, PCR20
  • 21. Mass Spectrometry Intact mass, comparison of Glycan variants. The difference in 56Da attributed to incorrect amino acid sequence21
  • 22. Hormone Receptor Binding by Biacore RU RU 80 80 70 70 60 60 50 50 40 DS Biosimilar 40 Resp. Diff. DP BiosimilarResp. Diff. 30 30 20 20 10 10 0 0 -10 -10 0 50 100 150 200 250 300 350 0 50 100 150 200 250 300 350 Time s Time s RU 90 Drug Substance Sample Lot No. KD (nM) % Difference 1 301 70 Biosimilar 2 399 3 412 4.40 1 415 50 Innovator 2 350 3 397 InnovatorResp. Diff. Drug Product 30 Sample Lot No. KD (nM) % Difference 1 202 Biosimilar 2 172 3 118 10 -1.64 1 138 Innovator 2 188 3 158 -10 0 50 100 150 200 250 300 350 Time s 22
  • 23. Finding the Differences by C-IEF 0.24 0.22 Main - 7.613 0.20 0.18 0.16 7.991 0.14 7.808 Absorbance 0.12 Blue - Biosimilar 0.10 Black - Innovator 0.08 7.524 0.06 0.04 7.419 0.02 8.145 0.00 6.60 6.80 7.00 7.20 7.40 7.60 7.80 8.00 8.20 8.40 8.60 8.80 9.00 9.20 9.40 Minutes SampleName: SB03iCE12-ADM3011P1 5C Lyo Date Acquired: 15-Dec-2010 20:16:15 -05:00 Result Id: 1581 SampleName: SB03iCE08-WL00039785 5C Lyo Date Acquired: 15-Dec-2010 18:55:04 -05:00 Result Id: 158023
  • 24. Carboxypeptidase Treatment 0.28 0.26 Main - 7.533 0.24 0.22 0.20 0.18 0.16 Absorbance 0.14 0.12 0.10 7.430 0.08 Blue - Innovator 0.06 Black - Biosimilar 7.333 0.04 7.249 7.659 7.159 7.731 0.02 0.00 -0.02 6.40 6.60 6.80 7.00 7.20 7.40 7.60 7.80 8.00 8.20 8.40 8.60 8.80 9.00 9.20 9.40 9.60 Minutes SampleName: SB07 iCE 05-WL00039785 9M RecoP3 Date Acquired: 21-Jul-2011 18:53:27 -05:00 Result Id: 4011 SampleName: SB07 iCE 09-ADM30011P1 9M RecoP1 Date Acquired: 21-Jul-2011 20:34:30 -05:00 Result Id: 401724
  • 25. Forced Degradation 0.130 0.120 0.110 0.100 0.090 0.080 7.265 Blue - Biosimilar Absorbance 0.070 Black - Innovator 7.382 0.060 0.050 7.138 Main - 7.531 6.996 7.481 0.040 0.030 6.927 7.603 0.020 7.709 7.805 6.798 0.010 7.906 8.041 0.000 -0.010 6.00 6.20 6.40 6.60 6.80 7.00 7.20 7.40 7.60 7.80 8.00 8.20 8.40 8.60 8.80 9.00 9.20 9.40 9.60 9.80 Minutes SampleName: SB09 iCE 12-ADM3001P1 30C Rec Date Acquired: 20-Sep-2011 21:19:46 -05:00 Result Id: 4716 SampleName: SB10 iCE 13-WL00039785 30C Rec Date Acquired: 20-Sep-2011 21:27:34 -05:00 Result Id: 475825
  • 26. Impact of Glycosylation? Blue- Innovator Black- Biosimilar26
  • 27. Simplify by De-sialylation? 0.30 0.28 0.26 0.24 0.22 0.20 0.18 Blue- Innovator 0.16 Black- BiosimilarAbsorbance 0.14 0.12 0.10 0.08 0.06 0.04 0.02 0.00 -0.02 3.50 4.00 4.50 5.00 5.50 6.00 6.50 7.00 7.50 8.00 8.50 9.00 9.50 Minutes 27
  • 28. N-Glycan Similarity 2200.00 G0F 2000.00 1800.00 1600.00 G1F Blue- Innovator 1400.00 G2F Black- Biosimilar 1200.00Energy 1000.00 Man5 G1F’ 800.00 600.00 G1’ 400.00 G0 G1 200.00 0.00 8.00 10.00 12.00 14.00 16.00 18.00 20.00 22.00 24.00 26.00 28.00 30.00 Minutes28
  • 29. Mass Spectrometry29
  • 30. Peptide Map30
  • 31. NOTE: Originators make ‘biosimilars’ every time there is a manufacturing process change Aranesp ® (Darbepoetin-alfa) MabThera®/Rituxan® (Rituximab) Enbrel ® (Etanercept)Ref: Schiestl et al. Nat. Biotechnol. 2011; 29: 310-312(Sandoz) 31
  • 32. Characterization of Commercial Batches ofDarbepoetin alfa from the EU Change in isoform distribution between two sets of batches (expiry date April 2010 and September 2010) Schiestl et al. Nat. Biotechnol. 2011; 29: 310-31232
  • 33. Characterization of Commercial BatchesMabthera®/Rituxan® (rituximab) •Shift in Glycosylation Profile and ADCC Potency• Differences/shift in glycosylation pattern results in different potency in cell-based assays• Product label remained unchanged –indicating comparable quality Schiestl et al. Nat. Biotechnol. 2011; 29: 310-31233
  • 34. Characterization of Commercial Batches of Enbrel • Shift in Glycosylation Profile • Differences/shift in glycosylation pattern • Product label remained unchanged –indicating comparable quality Schiestl et al. Nat. Biotechnol. 2011; 29: 310-31234
  • 35. Demonstrating Comparability in an Ideal World? Product heterogeneity is clearly understood, variants are easily isolated and characterized  Product variants and related impurities  Process related impuritiesSmooth manufacturing scale up, no process changes Methods ready to demonstrate comparability without development. “One size fits all” Enough time and a ‘crystal ball’ to know what to look for35
  • 36. What does This Look Like in the ‘Real World’?Biosimilars are “snowflakes”. No two are the sameIncomplete comparability characterizationExperience rapid time pressuresFinal formulation often undecidedManufacturing difficulties with scale upFast turn around in-process sample analysisRapid development and validation for ‘discriminating’ assaysNeed justification and risk assessment for observed differences36
  • 37. Other ‘Real World’ Observations IIStress stability studies (w/ multiple time points) neededMultiple lots of reference product often used. Understand impact of ref. product ‘shelf-life’ on results. Justify useReference product isolation procedure can impact resultsComparability continues even after releaseGMPs apply for biosimilar product developmentMeet with BOHs as early as possible to discuss your analytical control strategy
  • 38. Other ‘Real World’ Observations IIIProtein analysis requires an ‘integrated’ set of analytical methods Evaluate all domains and protein modificationsUse orthogonal analytical methods to confirm observations and expectations.State-of-the-art techniques are expectedRealize each analytical method has strengths and weaknesses: Spectral methods measure averages Qualitative vs. quantitative? Variable sensitivity etc.38
  • 39. Summary Biosimilar regulatory guidelines continue to evolve Demand for biosimilar CMC development continues to grow Demonstrating comparability requires extensive analysis pre- and post-clinically. Must completely characterize innovator product We are making progress linking some, but not all, biological properties to critical quality attributes; therefore,  Given a gradation of a biologics complexity, a one size fits all strategy for biosimilars will not be possible39
  • 40. Let us know how we can help you! DISCOVERY DEVELOPMENT COMMERCIALIZATION RESEARCH PRECLINICAL PHASE I PHASE III PHASE IV Efficacy Model Development/Biomarker Development Immunogenicity, PK, TK Immunotoxicity: CDC & ADCC Tissue Cross Reactivity Pharmacokinetics/Toxicity Viral Clearance Process Development Support, Biomanufacturing Support, Biosafety Testing In vivo/In vitro Biopotency Physicochem & Biological Characterization Health Economics Assessment Serum Production Reimbursement Clinical Feasibility Phase I to Phase III Clinical Trials Clinical Development: Target Population Clinical Development: Special Populations Stability and Release Outcomes/PE Studies Central Labs Data: Safety and Genotyping Post-Marketing Commitments Molecular Development (Program Management & Clinical) Regulatory Strategy, EMA/FDA Documentation Prep & Meeting Attendance, CTA/IND/BLA Support and Submission40