patient-first, science-based regulatory approaches for ......biocon has the science, scale, scope,...
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Sundar Ramanan, Ph.D.Vice President, Global Regulatory Affairs
May 13, 2019
Patient-first, Science-based Regulatory Approaches for Insulins
Biocon – Pioneer in Affordable Access to Biologics
40 years in Biotechnology
Expertise in multiple expression systems (e.g. Yeast, E.coli, CHO, SP2/0)
In 2019, Biocon’s products will improve ~2.6 million livesa
Glargine & rHI: ~2.5 million lives
Pegfilgrastim: ~ 26,000 lives
Adalimumab: ~ 24,000 lives
Trastuzumab: ~ 20,000 lives
“For us a blockbuster is being accessible to a billion patients” Kiran Mazumdar-Shaw
Patents filed*
~1,315Patents granted*
~1,100Registered
Trademarks*
~630
Biologics taken from Lab to Market
2 Novels & 6 Biosimilars
8
cGMP approvals from International regulatory agencies*
25+
Countries where our products are available
~120
Key regulatory approvals from US, EU, Japan, France, Brazil, Mexico, Turkey, GCC etc.
a. Number of lives is calculated based on volume supplied
Expertise in Insulins: > 15 years of serving patient needs
Insulin: 40+ countriesa
Insulin Glargine: 60+ countriesa,b
a. List of countries on fileb. Marketing authorization holder is Mylan in some countriesc. https://wayback.archive-it.org/7993/20170405222944/https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/OncologicDrugsAdvisoryCommittee/UCM431118.pdf
Biocon has the Science, Scale, Scope, Technology, and years of real world safety data
> 2 Billion doses; ~730 Million patient days exposure
rHuman InsulinInsulin Glargine
One of the largest Insulins provider
FDA precedentc: Use of 7.5 Million patient days of exposure toward the Totality of Evidence for the US approval of Zarxio®
Insulins• rHI, Basal and Rapid acting • Vials, pens and cartridges• Disposable and reusable pens
Question 1 (a): Considerations for BiosimilarityOutline
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1. Molecular complexity - Insulins can be completely characterized
2. Efficacy & Safety can be evaluated using in-vitro functional assays
3. Clinical pharmacology can also include efficacy (valid PD marker) and safety assessment
4. Minimal residual uncertainty with regards to immunogenicity
5. Considerations to address residual uncertainty with regards to immunogenicity
a) Utilize existing/available clinical evidence
b) Immunogenicity is not correlated with Insulin dose increase or adverse reactions
c) Consider uniqueness of Insulins in practice
d) Recommend specific clinical trial to address any product or patient related factors
6. Other considerations
Q1 (a): Considerations for Biosimilarity
Insulins are simple proteins – can be completely characterized
Image Source: BioEngage - https://www.amgenbiosimilars.com/expertise/highly-specialized-knowledge/
• Scientific and regulatory expectation must reflect the complexity of molecule
• Physiochemical & Functional assays are adequate to characterize the product and impurities
• Analytical characterization can adequately identify all residual risks (i.e. no unknown risks)
Consideration 1: Insulins are small and simple proteins
Q1 (a): Considerations for BiosimilarityConsideration 2: In-vitro methods can adequately assess the safety of Insulins
Physicochemical characteristics• Amino acid sequence• Secondary/HOS• Impurities and Variants
Biological activity
Efficacy
Safety
Metabolic Activity• Insulin Receptor B Binding• Insulin Receptor B
Phosphorylation• Glucose Uptake• Adipogenesis• Inhibition of stimulated lipolysis
Mitogenic Activity• Insulin Receptor A Binding• Insulin Receptor A
Phosphorylation• IGF-1 Receptor Binding• Cellular Proliferation
Efficacy & Safety can be determined using functional assays
STRUCTURE FUNCTION
rHuman InsulinCell growth & proliferation
P PGlucose
GLUT-4 Vesicle
GLUT-4
MAP Kinase/ERK Signalling PathwayPI-3K Signalling
Pathway
Cell Survival & Proliferation
Synthesis-Lipids,
proteins, glycogen
α α
β β
Insulin
1
4
2
3
α α
β β
IGF-1 receptor
1
2
Insulin receptor
3
Q1 (a): Considerations for BiosimilarityConsideration 3: Minimal residual uncertainty remains (Immunogenicity)
Immunogenicity
Clinical
Pharmacology
• PK comparability
• Validated PD
marker (GIR)
Non Clinical
• In-vitro Assays can
assess functions
with adequate
sensitivity (Efficacy
& Safety)
Quality(Analytical Similarity)
Structure-Function• Complete characterization is
possible
Totality of evidence required for biosimilarity can be addressed via Structure-Function analysis and PK/PD Comparability. Minimal uncertainty remains on Immunogenicity.
Residual Uncertainty
Insulin Antibodies (IA’s) and Insulin Resistancea:
- Multiple studies have shown absence of a correlation between IA’s & Insulin resistance
- In long-term follow-up studies of children with type 1 diabetes, neither the presence of insulin autoantibodies (IAA’s) nor the development of IA’s caused an increased need for insulin dose requirements
Insulin Antibodies (IA’s) and Hypoglycemiab:
- Many clinical studies have shown absence of significant correlation between IA’s and average glycemia
Q1 (a): Considerations for Biosimilarity
Insulin Antibodies are not correlated with (1) loss of efficacy or (2) safety issues
a. Radermecker et al., 2009, Diabetes Metab Res Rev 25:491–501; Lassmann-Vague et al., 1995, Diabetes Care 18:498–503; Salardi et al., 1995 Acta Paediatr 84:639–645;Tominaga et al., 1992, Diabetes Res. Clin. Pract. 18: 143–151; Fernandez et al., 1996, Diabet. Med 13:686–687; Keilacker et al., 1982, Metab. Res 14:227–232; Martinka et al., 1998, Vnitr Lek 44:577–581.
b. Wredling et al., 1990, Scand J Clin Lab Invest 50:551–557; Dozio et al., 1996, Diabetes Care 19:979–982; Francis et al., 1985, Diabet Med 2:89–94; Hubinger et al., 1988, Diabetes Res 7:65–69. Sakata et al., 1986, Immunol Invest 15:791–799.
Consideration 3: Insulins Immunogenicity & Risk to Patient Safety
Product Specific Factorsa:
- The insulin molecule is well established to have multiple T cell epitopes that can elicit an adaptive immune response
- Net immune response is a balance between opposing (effector & regulatory) T-cell responses
- Given identical AA sequence and T-cell epitopes are linear peptides, switch between the reference product & biosimilar is not expected to result in differential T-cell response
- Higher Order Structure (HOS) using NMR and X-ray crystallography can ascertain any structural difference with high degree of certainty
- In cases where the formulation is identical, no risks from excipients exist
Patient-related factorsb:
- Multiple long term clinical studies in T1DM ( >70% of patients had baseline anti-insulin antibodies [AIA]) and T2DM patients evaluating AIA formation after exposure to human Insulin and Insulin analogues indicate that AIA does not have a major impact on patient safety and efficacy
Q1 (a): Considerations for Biosimilarity
a. James, 2017 Diabetes 66: 2940-2941; Kurki et al., 2017, BioDrugs, 31(2):83-91.b. Data on file
Consideration 3: Insulins Immunogenicity & Risk to Patient Safety
Product and Patient-related factors suggest that AIA’s don’t cause a loss of efficacy or safety issues
One trial (N, ~300) can address any residual immunogenicity risks
TEAR rates from multiple studies have shown no impact on efficacy, safety or dosing
Comparative results should be viewed in the totality of evidence- Immunogenicity assessment should include NAb and its effect on glucodynamic effect (e.g., HBA1C and/or Insulin dose)
- Injection site reaction should also be evaluated
Q1 (a): Considerations for Biosimilarity
A single 300-patient study should be adequate to address any product and/or patient-related immunogenicity risks
Consideration 3: Recommendations to address any immunogenicity risks
Admelog FDA Medical Review 2017; Admelog EPAR 2017; Darwahl et al SORELLA 2 Results 2018; Garg et al SORELLA 1 Results 2017, Ilag et al, 2016, Basaglar FDA Medical Review 2014; Lusduna EPAR 2016
Q1 (a): Considerations for Biosimilarity
Products with multiple concentration:• Safety & Immunogenicity assessment of
one concentration is sufficient, along with a PK/PD assessment for an additional concentration based on scientific justification.
a. Humulin N, 70/30, R formulations US-PI; http://pi.lilly.com/us/HUMULIN-N-USPI.pdf; https://pi.lilly.com/us/humulin-r-pi.pdf; https://pi.lilly.com/us/humulin-r-pi.pdf (accessed 5/6/2019)
Consideration 4: Other considerations toward totality of evidence
Low concentration High concentration
PK / PD
Safety
Immunogenicity
PK/PD
Products with multiple formulations:• Immunogenicity assessment of the
formulation with the highest theoretical risk is sufficient.
• Safety & Immunogenicity can be extrapolated to other formulations.
Formulation 1(e.g. Soluble)
Formulation 2(e.g. Suspension)
Formulation 3(e.g. Mix)
Extrapolation Form 1
Extrapolation Form 2
Immunogenicity assessment in
one theoretically high risk
formulationSam
e A
dve
rse
R
eact
ion
*
Q1 (a): Considerations for Biosimilarity
Safety & Immunogenicity data from clinical trials with a different reference product (for OTC products) should be considered toward the totality of evidence for biosimilarity
Consideration 5: Other considerations toward totality of evidence
For OTC products, Safety and Immunogenicity data for the biosimilar product from foreign controlled study (even if the reference product is different) should be considered toward the totality of evidence, with scientific justification
Pharmacovigilance data must be considered toward the totality of evidence, with scientific justification
Question 1 (b): Considerations for InterchangeabilityOutline
1. Insulin is the only protein to be designated as OTC
2. Biosimilarity + Any given patient + Risk of diminishing efficacy
3. Additional considerations
Humulin N® Novolin N®
Novolin N
Humulin N
Novolin N
Humulin N
Despite large differences in the Product Characteristics• Under emergency situations the FDA allows rHI to be switched between manufacturers2
• Effective Therapeutic Range is the Same & Wide (dosage is Identical, unit-per-unit basis)• Designated as OTC by the FDA
Pharmacodynamics1 Humulin R Novolin R Humulin N Novolin N Humulin 70/30 Novolin 70/30
Onset 30 min 30 min NA 1-2 hr 50 min 30 min
Peak 3 hr 1.5 - 3.5 hr 6.5 hr NA 3.5 hr NA
Duration of Action NA NA NA 24 hr 23 hr up to 24 hr
1. Data from the respective RLD US PI2. https://www.fda.gov/Drugs/EmergencyPreparedness/ucm085213.htm
NA = Not available
Humulin is manufactured by Eli Lilly and Novolin is manufactured by Novo Nordisk
Q1 (b): Considerations for InterchangeabilityConsideration: Only therapeutic proteins with OTC rating (r-Human Insulin)Different characteristics that could impact PD does not result in clinically meaningful differences
Q1 (b): Considerations for InterchangeabilityConsideration: No incremental risk for interchangeability
No additional need for evidence between Biosimilarity & Interchangeability
QUALITYAnalytical Similarity
NONCLINICAL(Efficacy & Safety)
CLINICAL PHARMACOLOGY
(human PK/PD; Efficacy & Safety)
CLINICAL CONFIRMATION(Immunogenicity)
Same clinical effect for any given
patient
Risk in safety terms of diminished
efficacy
• Every patient currently takes the drug that is titrated to their needs
• Comparison of GIR equivalence proves drug is effective in any given patient
• Unlike mAb’s, loss of efficacy due to AIA is not a concern for diabetic patients
• Unlike mAb’s (weekly, monthly or longer), Insulins are injected daily (i.e. a single switch or a three switch study is not needed)
There are multiple reference products or biosimilars available to patients today, and these products are frequently switched with each other because of an OTC rating or other drivers, therefore:
- When a biosimilar is approved, it should be deemed as interchangeable to all the reference products
Q1 (b): Considerations for InterchangeabilityConsideration: Uniqueness of Insulins
Q2: Unique scientific considerations for continuous infusion pumps
All product related factors have been adequately addressed via totality of evidence for biosimilarity/interchangeability
No additional or incremental risk exists from the product
Product Compatibility studies are needed (i.e. compatibility study and extractable/leachable study)
Additional clinical studies do not add any value for the patients or address any specific safety risks
Product compatibility testing and Extractable/Leachable studies are adequate to ensure safety. No additional studies are needed.
Q3: Patient Experience
Patient experience data should be linked with clinical outcomes, i.e. safety, efficacy etc.
Patient preference data, should be limited to clinical outcomes
Policies should allow patient experience and/or patient preference data to be utilized toward enabling approval, access and/or adoption of biosimilars
Patient experience should allow for a greater access to biosimilars
Q4: Information resources for patients, clinicians, pharmacists, and other stakeholders
Level playing field for both the reference product and biosimilars – Any false and/or misleading information campaign should have meaningful consequences
– FDA must ensure that the promotional materials not include language that is suggestive or negative about biosimilars
Any educational and promotional materials casting aspersions on the biosimilarity and/or interchangeability should be discouraged
Enhanced education on storage and handling should mitigate Loss of Efficacy (LoE)– We request the FDA to discourage attribution of LoE to either the reference products, biosimilars or due to switching
between the two, without convincing evidence
FDA should enable fair, transparent, evidence based communication
Conclusions
Insulins are simple proteins and the regulatory requirements should be proportional to the complexity
Residual uncertainty can be accurately identified and quantified
Such residual uncertainty can adequately be addressed in a single clinical trial
The totality of evidence required for a biosimilar or interchangeable insulin is the same
–All biosimilar Insulins should be approved as Interchangeable products
Compatibility studies are necessary and sufficient to address any risks related to continuous infusion pumps
Patient experience data should enable quicker access to biosimilars
Patient-first, Science-based regulations ensure efficient development of biosimilar and interchangeable Insulins.