Post on 03-Sep-2020
Biotherapeutics –How to manage complexity?
Dr. Thomas Schreitmueller, Head Regulatory PolicyF. Hoffmann – La Roche Ltd, Basel, Switzerland
Disclosure – Conflicts of Interest
• Employed by F. Hoffmann – La Roche Ltd.• The relationship reported above will not impact my ability to
present an unbiased presentation
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The complexity of Biotherapeutics and the need for specific regulatory frameworks for
biosimilarsThe use of existing copies of biotherapeutic products that have not gone through an adequate development program is not recommended due to potential safety implications.
Biological products are highly complex – Generics approval pathways and practices do not apply
Adapted from: Steven Kozlowski; FDA
K
pyro-E
G
D
O
D
GO
D
pyro-E • Pyroglutamyl peptides
K
• C-terminal Lysine
D
D
D • Deamidation
O
O • Methionine oxidation
G
G• Glycation
• High mannose,G0,G1,G1,G2
• Sialylation
Modifications may result in approximately 108 potential variants
Biologics have the potential to induce an immuneresponse
Formation ofanti-drug antibodiesis the chief criterion for defining a biologic’simmunogenicity.
FDA. Guidance on Immunogenicity Assessment for Therapeutic Protein Products. 2014.
• All protein-based biologics have an immunogenic potential, i.e. they may be identified as ‘foreign’ by the patient’s immune system and cause an immune response.
• The consequences of such an immune reaction can range from transient appearance of anti- drug antibodies (ADAs) without any clinical significance to severe life-threatening conditions.
• Besides potentially causing immunogenicity-related adverse effects, ADAs may alter a biologic’s pharmacokinetic/pharmacodynamics properties and/or abrogate its therapeutic effect.
Immunogenicity can be defined as:The tendency of a biologic to induce an unwanted immune response or to induce immunologically related adverse events.
3. Packaging, Labelling and Distribution
2. Drug Product Process
1. Drug Substance Process
Biotherapeutics – Manufacturing Complexity
https://www.ich.org/products/guidelines.html
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WHA 67/20 is calling for strengthening regulatory systems mentioning biotherapeutic product (BTP) the first time in a WHA resolution
In reference to national regulatory capacity, the World Health Assembly approved this resolution on promoting the establishment of multinational collaboration, work sharing and cooperation between national and regional regulatory authorities in complex technical areas such as the regulation of biotherapeutic products in order to potentially overcome these constraints.
67th WORLD HEALTH ASSEMBLY (WHA)/A67 R20
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By approving this resolution, Member States recognized that access to biotherapeuticmedicines, including biosimilars, is important for patients in many countries and, through the resolution, urge all Member States to develop “solid, scientifically-based regulatory frameworks” and to use the World Health Organization (WHO) Guidelines as the foundation for these frameworks.
67th WORLD HEALTH ASSEMBLY (WHA)/A67 R21
WHA 67/21 is calling specifically for increasing access to biotherapeutic product (BTP) the first time in a WHA resolution
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Recommendation of 16th
ICDRA meeting in 2014*:
“…to strengthen the capacity of NRAs to assess and monitor the quality, safety and efficacy of biotherapeutics during the complete life-cycle of the product…”
*WHO Drug Information Vol. 28, No. 3, 2014
In the ICDRA 2014 recommendations member states wanted more from WHO
The WHO regulatory framework for biotherapeuticproducts
•Guidelines on the quality, safety and efficacy of biotherapeutic protein products prepared by recombinant DNA technology, WHO Technical Report Series, No. 987, Annex 4 pdf, 418kb
•Regulatory assessment of approved rDNA-derived biotherapeutics, Technical Report Series, No. 999, Annex 3pdf, 147kb
The WHO Guidelines on procedures and data requirements for changes to approved biotherapeutic products was adopted by ECBS in its 68th meeting in 2017. •Annex 3, TRS 1011pdf, 452kb
https://www.who.int/biologicals/biotherapeutics/biotherapeutic-products/en/
•Guidelines on evaluation of similar Biotherapeutic Products (SBPs), Annex 2, Technical Report Series No. 977, 2009pdf, 493kb
•WHO Questions and Answers: Similar Biotherapeutic Productspdf, 424kb
•Guidelines on evaluation of monoclonal antibodies as similar biotherapeuticproducts (SBPs), Annex 2, Technical Report Series No. 1004, 2016pdf, 221kb
ImplementationWHO Guidelines adopted by the ECBS 2009 have been instrumental in raising awareness of the complex scientific issues related to the licensing of similar biological products. Implementation of the guidelines has become an increasingly important tool in achieving regulatory convergence.
https://www.who.int/biologicals/biotherapeutics/similar_biotherapeutic_products/en/
The WHO regulatory framework for similar biotherapeuticproducts
The Basis of Biosimilarity is the «Totality of Evidence»as outlined in all relevant global regulatory guidelines incl. WHO and WHO reference countries
The use of existing copies of biotherapeutic products that have not gone through an adequate development program is not recommended due to potential safety implications.
S c i e n c e
Ana
lytic
al S
imila
rity
Pre-
clin
ical
Sim
ilarit
y
Clin
ical
Sim
ilarit
y
Phar
mac
ovig
ilanc
e
B i o s i m i l a r i t y
Prop
er Q
ualit
y Sy
stem
The Process Defines the Product
© Roche
DNA 1
Product 1
Product 2
Fermentation 1Purification 1
Purification 2
Fermentation 2
Cell line 1
Cell line 2
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DNA 2
Amino acid sequence
Vector 1
Vector 2
The same amino acid sequence
(perhaps the same DNA sequence)
(Probably) A different DNA-vector A different
recombinant production cell
line
A different production process
Different analytical methods
Different process à different product
A second manufacturer uses...
Biosimilar
Quality
Cross reference
Non-Clinical
Clinical Cross reference
Cross reference –class specific
Safety and efficacyIntegrated Biosimilarity
Exercise –Quality, Safety and Efficacy
3.Clinical
2. Non clinicalin vitro testing
(+specific in vivo if needed)
1. Quality (analytical) comparison, functional
aspects e.g. binding
Biosimilar?
Biosimilar?
Biosimilar?
Originator
Totality of Evidence/Stepwise Approach
Note: Unwanted immunogenicity can occur with any biologic including biosimilars- this can only be evaluated clinically
Applying the biosimilar concept-stepwise and comparative
Establishment of Similar Biotherapeutic Product (SBP) Guideline has increased – driven by WHO efforts
The history of regulatory frameworks for biosimilars
17
2004
EMA Overarching biosimilar guideline
(revised 2014)
EMANon-clinical/ Clinical
guideline(revised 2014)
2010 2015
WHOGuidelines on
biosimilars(Annex 2)
2009
FDAAbbreviated
approval pathway for biosimilars
(351(k))
FDABiosimilarity
scientific/qualityconsiderations
2014
FDABiosimilarity clinical
pharmacology (draft)
2005 2012
EMAProduct-class
specific guidelines(link)
EMAOverarching quality guideline (revised
2014)
WHOGuidelines on mAb
biosimilars(draft)
2016
EMAGuideline on
biosimilar mAbs(non-clinical/
clinical)
General EU Guidelines:
Overarching Guideline (CHMP/437/04)“Guideline on Similar Biological Medicinal Products”
Non-clinical/clinical Guidance Quality Guideline
Insulin Somatropin G-CSF Epoetin IFN-α LMWH mAbs IFN-β Follitropin
Class-specific EU Guidelines: non-clinical/clinical aspects:
2006 2006 2006 2006 2009 2009 2012 2013 2013
Revision ongoing, draft GL
target Q1 2018
Revision ongoing-concept
paper target Q3 2018
Revision 2012
Revision 2015
Revised 2014
Revised 2015
Revised 2014
Revision 2016
Revision being
considered 2018 TBD
Revision planned-concept paper due
Q3 18
The EU regulatory frameworks for biosimilars
12 withdrawn prior to opinion
2 negative opinions
43 Positive opinions
3 withdrawn after
approval
39 hold a current
Marketing Authorisation
1 awaiting EC decision
14 Unsuccessful applications
Unsuccessful applications (withdrawals/negative opinion) suggest that the system is working as it is able to distinguish products that should not be approved from those that should.
57 Marketing Authorisation Applications
Biosimilars applications submitted to EMA, approved, withdrawn or rejected
WHO. Guidelines on biosimilars 2009. http://www.who.int/biologicals/areas/biological_therapeutics/BIOTHERAPEUTICS_FOR_WEB_22APRIL2010.pdfEMA. Overaching guideline on biosimilars 2014: CHMP/437/04 Rev 1. EMA. Guideline on immunogenicity 2007: EMEA/CHMP/BMWP/14327/2006.
FDA. Guidance on biosimilarity 2015. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM291128.pdfFDA. Guidance on quality 2015:Quality Considerations in Demonstrating Biosimilarity of a Therapeutic Protein Product to a Reference Product (PDF - 144KB)
FDA. Draft guidance, Q&A on BPCI Act 2015:Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009 Guidance for Industry (PDF - 107KB)
Biosimilar regulatory framework comparison
Regulatory Framework
Similarity concept
Substitution/Interchange-
ability
Extrapolation across
indications
Immuno-genicity
Naming/Pharmacovigilance Reference Product
EMAConcept created by EU
Decided at member state level
Ok if scientifically justified for each condition
Needs to be studied in humans pre- and post approval
EU uses INN system and Trade Name to distinguishBiotherapeuticProducts while the US is using a 4-letter suffix with the non-proprietry name--------------PV is required for all products in EU, US and in accordance with WHO guideline-------------Requires adequate monitoring process to differentiate AEs in the marketplace –but is not specified
Reference product must be approved in the EEA but possible to use non-EEA authorized comparator
WHO
Follows EU principles; however, WHO has not issued product specific non-clinical or clinical guidelines
Not addressed in WHO guidance
Reference product must have been licensed on basis of a full dossier
FDASimilar concept to EU except no product specific guidance.
Interchange-ability is a higher standard than Biosimilarity
Data from non-US with acceptable bridge to the US licensed product
WHO-specific EMA-specific FDA-specific Common Guidance
FDA: Interchangeability General Principles
• Two step process requires:– Demonstration of biosimilarity to reference
product– Demonstration of interchangeability
• Interchangeability a higher standard;requires clinical studies demonstrating that the biosimilarproduct:
– Provides the same clinical result as the referenceproduct in any given patient
– Can be switched back an forth with thereference product without greater risk than the risk of using the reference product alone
• Interchangeable product may be substituted forthe reference product without intervention of thehealthcare provider
The Theory of Biosimilarity
The use of existing copies of biotherapeutic products that have not gone through an adequate development program is not recommended due to potential safety implications.
McCamish M and Woollett G. mAbs 2011;3(2):209-217.
The variability of the quality attributes of the reference product defines the acceptable variability of the bio-similar …
…resulting in biosimilar products that are highlysimilar to the reference product
Schellekens H et al. Eur J Hosp Pharm Pract 2004; 3:43-47.Brockmeyer C et al. Eur J Hosp Pharm Pract 2009; 15:34-40.
“Copy epoetins” from 8 different manufacturers (marketed outside US/EU)
Eprex® reference standard
Eprex®BS EPO 1 Eprex®BS EPO 2
Not similar to reference product No clinically relevant differences
The Practice of Biosimilarity
Infliximab approval (Flixabi®) in the EU
“Based on the CHMP review of data on quality, safety and efficacy, the CHMP considers by majority decision that the risk-benefit balance of Flixabi in the treatment of rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and plaque psoriasis in adult patients and Crohn’s disease and ulcerative colitis in adults and in children and adolescents aged 6 to 17 year is favourable and therefore recommends the granting of the marketing authorisation”
Evaluation Conclusion from CHMP
Adapted from CHMP assessment report EMA/CHMP/272283/2016
“In conclusion, the undersigned CHMP members consider the benefit/risk balance of Flixabi to be negative since biosimilarityto Remicade has not been established.”
DIVERGENT POSITIONS dated 1 April 2016 Flixabi EMEA/H/C/004020/0000
Agnes Gyurasics (HU)Daniel Brasseur (BE)Daniela Melchiorri (IT)Greg Markey (UK)Jana Schweigertova (SK)Jens Heisterberg (DK)Karsten Bruins Slot (NO)Koenraad Norga (COM)Kristina Dunder (SE)Nevenka Trsinar (SI)Outi MakiIkola (FI)Pieter de Graeff (NL)Fatima Ventura (PT)Robert Hemmings (COM)
• For Flixabi an increased incidence of ADA was observed both in the Phase 1 and the Phase 3 studies, and it has not been substantiated that the difference was an artefact due to – for example – problems with the interpretation with the immunogenicity assays that were used.
• In the Phase 3 trial, which was conducted in patients with rheumatoid arthritis, the efficacy of Flixabi, whilst meeting the pre-specified equivalence margins, was consistently, although not universally, estimated to be lower than that of Remicade.
• It is noteworthy that the Phase 3 study showed that the efficacy, regardless of treatment group, was significantly lower in ADA positive patients than in ADA negative patients.
• It is not possible with reasonable certainty to exclude that the estimated reduction in efficacy of Flixabi was the result of the higher incidence of ADA. In this regard,
Based on these differences the Flixabi® EPAR reveals a divergence of opinions on biosimilarity of European regulators:
DIVERGENT POSITIONS dated 1 April 2016 Flixabi EMEA/H/C/004020/0000
Complex Mode of Action of mAbs may involve various mechanisms
TargetCells
ComplementC1q
Effector cells: NK
cells, MΦs
C) Complement dependent cytotoxicity (CDC)
B) FcγR mediated Antibody dependent cellular cytotoxicity (ADCC)
A) Direct cell death
Dendritic cell
D) Adaptive cellular immunity
Activated T-cells
Examples non-clinical:
• The binding activities of some batches of SB2 were found to be slightly higher than the upper limit of the similarity range.
FcγRIIIa of SB2 114 -141% compared to 77 - 108% for EU Remicade
FcγRIIb of SB2 105 -120% compared to 99 - 104% for EU Remicade
FcRn of SB2 105 -120% compared to 88 - 105% for EU Remicade
Flixabi® EPAR : The analytical and non-clinical assessment indicated (significant) differences between the biosimilar and the reference product
Adapted from CHMP assessment report EMA/CHMP/272283/2016
Attributes(Analytical method) Result
Ratio of G0 (Oligosaccharide, (%))
Lower G0 translated to lower binding to FcγRIIIa binding
Ratio of FcγRIIIa binding(Relative binding, (%))
Data presented by Celltrion during CASSS CMC Strategy Forum Brazil, 2015
Remsima®: The analytical and non-clinical assessment indicated (significant) differences between the biosimilar and the reference product
Comparison of FcγRIII-binding of Remicade®, Remsima® and Flixabi® clearly indicates:
Biosimilars are (highly?) similar but not identical…
Remsima® Remicade® Flixabi®
% FcγRIII-binding100
Schematic representation not representing concrete values
…and is raising important questions
% FcγRIII-binding100
Schematic representation not representing concrete values
• Are Remsima® and Flixabi® similar?• Are longterm safety and efficacy profiles comparable?• Can patients simply be switched from Remicade® to
Remsima® to Flixabi®?• Can we simply apply automatic substitution?
Remsima® Flixabi®
The Practice of Biosimilarity –
The Consequences
Risk mitigation strategies – Crucial for all Biologics/ Biosimilars
MoreDefined
Uncertain
Label Populations
OptimizedIndividualized
Populations and Endpoints
Ben
efit/
Ris
kSi
mila
rity
How to bestManage thistransition?
What to consider?
PV/Benefit Risk Management Plans
Adapted from Thomas Lundgrenn (DIA QPPV Forum, 17-18 April 2013)
Pharmacovigilance is key for allbiologics
Regulatory guidanceon biosimilar naming and AE reporting
EMA
• Biosimilars are given the same INN asthe reference product.
• Brand name and batch number is required for reporting of suspected adverse reactions.
FDA • INNs of biologics are given an identifier (four- letter suffix) unique to each product.
Robust pharmacovigilance is important for detection of rare and/or unexpected safety issues.
FDA. Nonproprietary Naming of Biological Products - Guidance for Industry. 2017. EMA. Guidelines on good pharmacovigilance practices (EMA/529641/2016). 2016. EMA. What does the black triangle mean? 2013.
INN, international non-proprietary name
• Rare and/or unexpected safety issues often become apparent only after a medicinal product has been on themarket.
• All new biologics, including biosimilars, require “special monitoring” by the EMA to encourage reporting of suspected side effects (indicated by ”▼” on SmPC andPIL)
• Unique identifyers that distinguish products (e.g., biosimilars from their reference products) are a prerequisite for appropriate reporting of adverse events in the post-marketing setting.
Switching between the Reference Product and it’sBiosimilars will be a Scenario in clinical Practice
Treatment-experienced patientsSwitching a patient to a biosimilar when he or she is already on a treatment program with the reference product or vice versa
Treatment-naïve patients
Biosimilar is prescribed to treatment-naïve patients.
Renwick et al. Lancet Oncol. 2016 Jan;17(1):e31-8. FDA: Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009, April 2015
No clinically meaningful differences are expected, since approved biosimilars have undergone therapeutic equivalence evaluations in treatment-naïve patients.
Will require additional clinical evidence going beyond the biosimilarityassessment otherwise the consequences of switching are unknown.
Cantini et al. Failure of bio-IFX after switching fromre-IFX in Behçet’s disease patientsEur. J. Rheumatology 2017
• Behçet’s disease (BD) is a chronic, relapsing, systemic vasculitis ofunknown cause involving veins and arteries of all sizes. Eye andneurological inflammatory involvement (neuro-Behçet) representsevere clinical manifestations of BD that may lead to blindness orpermanent neurological deficits.
• Our experience with the 3 BD patients who were successfully treatedwith re-IFX and who experienced recurrence of uveitis and of neuro-Behçet soon after switching to bio-IFX appears to reinforce skepticismregarding the exchangeability and automatic substitution of referencere-IFX with the biosimilar drug.
• In the absence of a valid explanation, we could only hypothesize that the rapid failure of bio-IFX in our 3 patients might be related to the development of ADAs against IFX.
Cantini et al. Failure of bio-IFX after switching from re-IFX in Behçet’s disease patients , Eur J Rheumatol 2017
Medical Associations Considerations on Switching and Position on
Pharmacy-mediated Interchangeabiliy
Switching – ESMO
The Danish Medicine Council’s recommendations for rituximab1. New patients - rituximab naive:
The expert committee believes bx. rituximab can be used
2. Patients who previously have been treated with MabThera - and after a break in the treatment are to resume biological treatment:The expert committee believes that there are no significant arguments for not using bx. rituximab
3. Patients who are currently undergoing treatment with Mabthera: The expert committee believes that change of drug during the introduction treatment may create uncertainty in the dialogue with the patients. Also new side effects or progression - even if not caused by that change could complicate the situation for the patients - who already are in a difficult phase of their disease and treatment.The expert committee recommend NOT to change the treatment/drug in the introduction phase
Biosimilar Market Dynamics in the EU and Considerations for Sustainability
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Sustainability for the Biologics/Biosimilars –A stong and focused regulatory system is key
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47Adapted from: IQVIA Advancing Biosimilar Sustainability in Europe, A Multi Stakeholder Report, September 2018
A Multi-Stakeholder Definition of Sustainability for the Biologics/Biosimilars Marketplace
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49Adapted from: IQVIA Advancing Biosimilar Sustainability in Europe, A Multi Stakeholder Report, September 2018
Tendering Scenarios – Impact on Sustainability
Conclusions
Conclusions I
• Regulations for biosimilars are globally harmonized in that:
– They do not accept the generics approach for biologics– They all demand comparative assessments against one
reference product registered as NBE– Expect analytical differences between the reference product
and the biosimilar product and thus– Suggest a stepwise similarity assessment including head to
head pre-clinical and clinical studies as well– Permit extrapolation when scientifically justified.– Require robust pharmacovigilance
• The decision on similarity is based on the «totality-of-the-evidence»
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Conclusions II
Patients deserve the best available treatment for better outcomes and cure.
Biosimilars are a valid treatment option when approved according to properly implemented standards
Switching decisions by the treating physician should be based on the patient situation and on the availability of data from robust similarity and switching relevant assessments
Uninformed or enforced switching of patients should be avoided through proper procurement strategies and the respective management of formularies
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Thank You !