Presented at DCAT Week 2014
March 10-14, 2014
New York, NY
Reducing Technical & Regulatory Uncertainty in Biosimilar Development
1
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
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
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
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
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
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
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
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08.2007 12.2008 05.2010 09.2011
Expiry Date
Unfucosylated G0
[% of glycans]
60
80
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120
140
08.2007 12.2008 05.2010 09.2011
Expiry Date
ADCC Potency
[% of reference] Post-
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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)
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
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External review should be leveraged but need internal review
Common pitfalls and symptoms
Inadequate focus on TPP, QTPP (analytics) & market research
Functional check-box
Cut-paste approach to clinical trials
Rush to clinical
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Clinical Trials (WHO): Biosimilar
11
96
Clinical Trails (US): Biosimilar
12
28
ClinicalTrail.Gov: Biosimilar
13
‘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”
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http://www.ft.com/cms/s/2/dcad130c-a8fb-11e2-a096-00144feabdc0.html#axzz2TqDBcYlB
http://www.biosimilarnews.com/roche-doesnt-see-a-threat-from-biosimilars-till-2015
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. (ClinicalTrials.gov 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 (ClinicalTrials.gov Identifier: NCT01419665)
• 618 subjects; estimated completion date March 2014
Phase III
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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 (ClinicalTrials.gov 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 (ClinicalTrials.gov 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 (ClinicalTrials.gov Identifier: NCT01955733)
• 250 subjects; Estimated completion date December 2016
Phase III
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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 (ClinicalTrials.gov 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 (ClinicalTrials.gov 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
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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
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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
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Multiple disciplines & stakeholders
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
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Thank You!
Insight Advice & Solutions LLC
6615 Hunter Trail Way
Frederick, MD 21702
1 240 457 7064
Ajaz S. Hussain, Ph.D.
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