Reducing technical and regulatory uncertinty in biosimilar development


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Reducing risk of Biosimilar product development requires early attention to evidence development and effective communication to multiple stakeholders. Skill set for effective leadership and management, in the US market context, includes ability to: (1) Overcome the ‘blind spots’, (2) Analysis of knowledge, and (3) Evidence logic & communication. This presentation makes these points while comparing the EU and the USA regulatory context and the challenges of integration across multiple scientific and clinical disciplines.

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Reducing technical and regulatory uncertinty in biosimilar development

  1. 1. Presented at DCAT Week 2014 March 10-14, 2014 New York, NY Reducing Technical & Regulatory Uncertainty in Biosimilar Development 1
  2. 2. Background Previous speakers have covered • Market overview, manufacturing technologies, and recent developments in this area • The current status of US regulatory pathway for biosimilars and related issues on a state level In this presentation we will review • Similarity and differences in the US and EU regulatory framework • With the objective to understand how to reduce technical and regulatory uncertainty in the US market context 2
  3. 3. Reduce technical and regulatory uncertainty in Biosimilar Development • Reduce cost and time of biosimilar development and enhance market penetration Why • Understanding the basis of approvals of selected products and established and emerging guidelines and open issues How • Technical and organizational considerations; analytical characterization, PK/PD studies, and clinical trial designs to address residual uncertainty What 3
  4. 4. Determinants of success Cost and time of development Analytical characterization of reference product Clone selection and design of upstream and downstream process Comparability & similarity; residual uncertainty PK/PD, Clinical trial design, human factor analysis Market penetration • Indications & evidence • Clinical data vs. extrapolation across indications • Interchangeability (USA) 4
  5. 5. Basis of approvals of selected products US FDA • Omnitrope® (Sandoz) • Tbo-filgrastim® (Teva) • Generic Enoxaparin (Sandoz- Momenta and Watson- Amphastar) Products • Process & Analytical • Clinical Evidence EMA • Omnitrope® (Sandoz) • Tbo-filgrastim® (Teva) • Biosimilar Enoxaparin (none- approved yet) • Other products Products • Process & Analytical • Clinical Evidence 5
  6. 6. Established and emerging guidelines US FDA • General (e.g., ICH) • Biosimilar (Emerging) • Product specific (??) Guidelines • Process & Analytical • Clinical Review process EMA • General (e.g., ICH) • Biosimilar (Established) • Product specific (Yes) Guidelines • Process & Analytical • Clinical Review process 6
  7. 7. TPP & QTPP •Why add TPP? What is the specific purpose of TPP & QTPP in biosimilar development? •How many lots; when to characterize? How to leverage lot to lot variability in the reference medicinal product? •Understanding clinical relevance Which differences are acceptable while ensuring ability to demonstrate similarity? 7
  8. 8. QTTP • Define the targets for biosimilar development – Prior-knowledge (structure function, clinical,..) & RLD • Define ‘similar’ - acceptance criteria – Clinical endpoints & variability in reference product • QTPP should identify attributes most relevant – Facilitates development of meaningful target & acceptance criteria 8 0,0 0,4 0,8 1,2 1,6 2,0 08.2007 12.2008 05.2010 09.2011 Expiry Date Unfucosylated G0 [% of glycans] 60 80 100 120 140 08.2007 12.2008 05.2010 09.2011 Expiry Date ADCC Potency [% of reference] Post- Shift Pre-Shift Pre-Shift Post- Shift Schiestl, M., et al.: Acceptable Changes in Quality Attributes of Glycosylated Biopharmaceuticals. Nature Biotechnology, 29: 310-312, 2011 “This [enoxaparin] approval represents a major development in US regulatory science and policy that will likely affect several other complex drug products...the extensive analytical characterization, as carried out for enoxaparin, will be important in the evaluation of protein products and may help to reduce the scope and extent of animal and clinical studies for biosimilars.” Sau Lee, et. al., Scientific Considerations in the Review and Approval of Generic Enoxaparin in the United States. Nature Biotechnology. Volume 3, 220-226 (2013)
  9. 9. Stepwise approach Analytic characterization before in-vivo non-clinical and then clinical studies In EU adequacy of analytic characterization evaluated during MAA In US a step wise review approach has been established Companies with internal systems such as ‘QbD development’ can benefit 9 External review should be leveraged but need internal review
  10. 10. Common pitfalls and symptoms Inadequate focus on TPP, QTPP (analytics) & market research Functional check-box Cut-paste approach to clinical trials Rush to clinical 10
  11. 11. Clinical Trials (WHO): Biosimilar 11 96
  12. 12. Clinical Trails (US): Biosimilar 12 28
  13. 13. ClinicalTrail.Gov: Biosimilar 13
  14. 14. ‘Biosimilar rituximab development a rocky road’ Roche does not see a threat from biosimilar (rituximab) until 2015 “Samsung and Teva both suspended their Phase III programs in October 2012 within months of starting them” One reason for the delay – clinical considerations; challenge of extrapolation across indications “Totality of evidence” Sandoz and Boehringer are both already running Phase III trials, placing them ahead of Celltrion in the race” 14
  15. 15. Sandoz Trials: Biosimilar rituximab • A Randomized, Double-blind, Controlled Study to Evaluate PK, PD, Safety and Efficacy of GP2013 and Rituximab in Patients With Rheumatoid Arthritis Refractory or Intolerant to Standard DMARDs and One or Two Anti-TNF Therapies. ( Identifier: NCT01274182) • 164 subjects estimated completion date April 2012 Phase I/II • A Randomized, Controlled, Double-Blind Phase III Trial to Compare the Efficacy, Safety and Pharmacokinetics of GP2013 vs. MabThera® in Patients With Previously Untreated, Advanced Stage Follicular Lymphoma ( Identifier: NCT01419665) • 618 subjects; estimated completion date March 2014 Phase III 15
  16. 16. Boehringer Ingelheim Trials: Biosimilar rituximab •A Randomized, Double-blind, Parallel-arm, Phase I Study to Evaluate the Pharmacokinetics and Pharmacodynamics of BI 695500 vs. Rituximab (MabThera) Induction Immunotherapy as a First-line Treatment in Patients With Low Tumor Burden Follicular Lymphoma ( Identifier: NCT01950273) •90 subjects; Estimated completion date January 2015 Phase I •Efficacy, Pharmacokinetics, and Safety of BI 695500 Versus Rituximab in Patients With Moderately to Severely Active Rheumatoid Arthritis: a Randomized, Double-blind, Parallel Arm, Multiple Dose, Active Comparator Trial ( Identifier: NCT01682512) •360 subjects; Estimated completion date January 2016 •Safety and Efficacy of BI 695500 in Patients With Moderately to Severely Active Rheumatoid Arthritis: an Open-label Extension Trial ( Identifier: NCT01955733) •250 subjects; Estimated completion date December 2016 Phase III 16
  17. 17. Celltrion Trials: Biosimilar rituximab • A Phase 1, Multicenter, Open-Label, Single-Arm Study to Evaluate the Initial Safety, Pharmacokinetics, Pharmacodynamics, and Efficacy of CT-P10 Given in Combination With Dexamethasone, Cytosine Arabinoside, and Cisplatin (DHAP) in Patients With Diffuse Large B-Cell Lymphoma as Second-Line Chemotherapy ( Identifier: NCT01534949) • 10 Subjects; currently recruiting • Phase 1, Randomized, Controlled, Multicenter, 2-Arm, Parallel-Group, Double-Blind Study to Demonstrate the Equivalence of CT-P10 to MabThera With Respect to the Pharmacokinetic Profile in Patients With Rheumatoid Arthritis • 147 subjects; Estimated primary completion date August 2013 • An Open-Label, Single-Arm, Maintenance Study to Demonstrate Long-Term Efficacy and Safety of CT-P10 in Patients With Rheumatoid Arthritis Who Were Treated With Rituximab (MabThera or CT-P10) in Study CT- P10 1.1 ( Identifier: NCT01873443) • 102 subjects; Estimated primary completion date September 2014 Phase I • A Phase 3, Randomized, Parallel-Group, Active-Controlled, Double-Blind Study to Compare the Efficacy and Safety of CT-P10 With MabThera, Each Administered in Combination With Cyclophosphamide, Vinc... (EudraCT Number: 2011-002813-12) • Study terminated Phase III 17
  18. 18. The totality of evidence Proven comparability in the most sensitive indication are the key to secure (extrapolation of) indications (achieve TPP) A greater degree of analytical comparability & RLD variability informing on remining uncertinty Design of manufacturing process and controls to deliver a product conforming to QTTP 18
  19. 19. Key areas for consideration Overcoming the ‘blind spots’ • Sampling and statistical criteria (starting with RLD samples) Analysis of knowledge • Pertaining to analytical characterization and comparability acceptance criteria Evidence logic & communication • Argumentation is a central means by which the community assesses the promise of conjectures and the validity of claims 19 Multiple disciplines & stakeholders
  20. 20. Organizing for success Early investment in analytics and understanding variability in RLD TPP & QTPP in the context of residual uncertainty Review/challenge/integration system that does not impede development Design of clinical trials to address scientific and clinical (market) uncertainty 20
  21. 21. Thank You! Insight Advice & Solutions LLC 6615 Hunter Trail Way Frederick, MD 21702 1 240 457 7064 Ajaz S. Hussain, Ph.D.