What next?...Slide by Peter Richardson, EMA, EBG Conference London 2016 Biosimilars in the pipeline...
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What next? • Manufacture the biosimilar product – Design manufacturing process to match QTPP – Full quality dossier required. – Use state of the art technologies – In accordance with relevant ICH and CHMP guidelines – Targeted development of biosimilar to match the reference product – Careful consideration to the manufacturing process as the process defines the product e.g. host cell line, transfection process, cell culture media, hold times, drug product excipients, primary packaging
Transcript of What next?...Slide by Peter Richardson, EMA, EBG Conference London 2016 Biosimilars in the pipeline...
What next?
• Manufacture the biosimilar product– Design manufacturing process to match QTPP– Full quality dossier required.– Use state of the art technologies– In accordance with relevant ICH and CHMP guidelines– Targeted development of biosimilar to match the reference product– Careful consideration to the manufacturing process as the process
defines the product e.g. host cell line, transfection process, cellculture media, hold times, drug product excipients, primary packaging
And then – Demonstrate Comparability?• Comprehensive analysis of the biosimilar and the reference product
– Designed to show similarities and potential differences in quality– Side by side analysis using sensitive and orthogonal methods– Final commercial product
• Not expected that all quality attributes of biosimilar will be identical to reference product but:– Differences need to be justified– Only acceptable if no impact on clinical performance– Particular attention to attributes that impact potency and immunogenicity
Ultimate objective: demonstrate similarity to the reference
product
Assessing biosimilarity – protein structureProtein structure
Primary amino acid sequence should be the same as the referenceComparable higher order structure
Assessing biosimilarity
• Amino acid substitution• N- and C- terminal changes• Mismatched S-S bonds• Altered folding• Truncation• Aggregation• Multimer dissociation• Denaturation
• O- linked glycosylation• N-linked glycosylation• Methylation• Oxidation• Acetylation• Deamidation• Carboxylation
Post translational modifications need to be characterized
Presence of glycosylation structures/variants may be immunogenic
Protein heterogeneity
Presenter
Presentation Notes
Heterogeneous nature of biosimilar and reference to be considered during comparability exercise
Typical physiochemical biosimilarity exercise
Biological activity• Variety of different assays should be used• Complementary or orthogonal approaches to
overcome limitations of single bioassay• Assays – sensitive, specific and discriminatory• If product has more than one mechanism of action
all functional activities should be evaluated e.g. receptor binding and activation
Receptor binding(ELISA/SPR)
Cell based assaysFunctional assays
ApoptosisADCC
C1q bindingCDC
FcyRI bindingFcyRII bindingFcyRIII bindingFcRn bindingBiological assays confirm
Quality of productIntegrity of higher order structure
Mechanisms of action (Presence of expected functions, absence of new functions)
Potential effects of post-translational modifications
Quality comparability exercise : case study
Presenter
Presentation Notes
Case studies performed at WHO workshop- biosimilar candidates MAB Ranges of different quality attributes compared- relating to glycosylation, modifications and biological functions Candidate 1- results within variability of reference- any differences are minor and do no affect bioassay results Candidate 2- nearly all quality attributes of biosimilar are within range except for one glycosylation structure and ADCC activity is four times higher. Known that ADCC is essential part of MOA this candidate could be more potent- difference in critical function- standalone approach may be more appropriate
Non-clinical studies required for Biosimilars• Non-clinical studies performed before clinical trials• Commence with in-vitro studies and then, if necessary, continue with in-vivo
studies• Studies required will depend on the number of relevant quality differences
observed
Presenter
Presentation Notes
Tests should be comparative, designed to be sensitive enough to detect differences in response not just assess the response per se.
Clinical studies required for Biosimilars
• Tailored clinical testing programme • Stepwise approach: PK/PD followed by clinical
efficacy and safety • Choice of population for PK studies must be
justified• Comparative PK/PD studies may be sufficient
along with immunogenicity data (e.g. surrogate marker)
Presenter
Presentation Notes
Target population- most sensitive population in which any differences in clinical end points can be detected. Product specific GCSF guidelines – new concept paper – confirmatory CT may not be necessary since structure and biological activity is well characterisible and PD markers are available (absolute neutrophil count). Updated guideline expected to waive this requirements Insulin: demonstration of PK/PD profiles is the mainstay of proof of similar efficacy. Endpoints in efficacy study (HbA1c) not generally considered sensitive enough to detect differences
Efficacy trials
• Efficacy trials are designed to investigate if there are no clinically meaningful differences between the biosimilar and reference, they are not designed to establish patient benefit
• Patient benefit established by reference product, need to demonstrate similar safety and efficacy
• Equivalence design • Most sensitive patient population (in order to detect
differences)• Confirmatory clinical efficacy may not always be a pre-
requisite (e.g. concept paper for Filgrastim)
Presenter
Presentation Notes
Equivalence- design: response differs by an amount which is clinically unimportant. The biosimilar is neither inferior or superior. Adequately powered, randomised, parallel group, double blind Most sensitive population – population in which key differences in efficacy and safety are most likely to be detected.
Clinical safety• Captured during initial PK/PD studies and pivotal
efficacy studies• Immunogenicity of biologicals well known• Product related causes include protein aggregates,
attachment of sugars that are not present in humans, host cell proteins
• Safety data includes immunogenicity testing of biosimilar and reference (up to 1 year in a chronic condition) in order to identify any differences between the biosimilar and reference
• Pharmacovigilance and risk management activities necessary during the post-authorisation phase
Indication extrapolation
• Reference product usually has more than one indication
• When biosimilar comparability has been shown in one indication, extrapolation of clinical data to other indications possible if justified
• Consider in light of ‘totality of data’, mechanism of action and potential risks in patient populations
• Extrapolation of immunogenicity data from studied indication/route of admin must be justified
• HCPs should consult EPAR for details on clinical data provided
Presenter
Presentation Notes
Mechanism of action- AS may interact with different receptors in different indications, As has more than one active site and sites have different impact in different populations Studied indication is not sensitive for differences in aspects relating to S and E. Otherwise additional clinical studies required.
Indication extrapolation: ControversiesInfliximab biosimilar (CT-P13)
• Differences in afucosylated glycan structures, FcyRIIIa binding, and in a highly sensitive antibody-dependent cell mediated toxicity assay (ADCC)
• Clinical studies: patients with RA and AS
EMA concluded assay was not representative of physiological situation and allowed extrapolation to UC, CD, PsA and PsOHealth Canada: ADCC may be an active mechanism in IBD but not in rheumatic diseases - extrapolation not recommended for UC and CDFDA: Accepted extrapolation to all indications approved for the reference product Remicade
Pharmacovigilance of Biosimilars
• As with any ‘new’ medicine additional PV monitoring applies
• Remains under additional monitoring for ~5 years or until the EMA’s Pharmacovigilance Risk Assessment Committee (PRAC) decides to remove it from the list.
• Biological medicines should be identified in suspected adverse reaction reports with respect to name and batch number
Presenter
Presentation Notes
Brand name and batch number should be recorded at all levels in supply chain from manufacturer release, prescription, dispensing and patient administraion
Pharmacovigilance: Importance of traceability for all biological
medicines
• Inherent variability in large molecular weight structurally complex protein molecules (batch to batch from same manufacturer)
• Complex manufacturing process is specific to each manufacturer and will shape quality, safety and efficacy profile
• Changes in manufacturing processes – may impact product quality. Not always possible to predict immunogenicity as a result of manufacturing change
Naming of biosimilars
• In the EU, biosimilars have the same INN as their reference
Any biological medicine prescribed, dispensed or sold should be clearly identifiable
(brand name or INN plus name of MAH). This will also ensure
substitution by pharmacists does not inadvertently occur when the
medicine is dispensed by a pharmacist
Biological medicines can exhibit variability and therefore biological
medicines which have the same INN should not be
considered to be identical
Naming of Biosimilars
WHO - INN biological qualifier proposal• Voluntary scheme• Random code follows INN• Code - differentiate biological drug
substances manufactured by different processes
• Aims to aid in the minimisation of errors in prescription, dispensing, pharmacovigilance and international transfer of Rxs
• Will prevent proliferation of national qualifier systems
• Scheme has generated controversy• Impact assessment on scheme
implementation to be carried out
FDA – draft guidance on Nonproprietary naming of biological products
• Shared non-proprietary names not appropriate for all biological products
• Non-proprietary name will include FDA designated suffix
• Aims to identify biological products to prevent inadvertent substitution and improve pharmacovigilance
• ?? if interchangeable products will share same suffix as reference
• Public consultation now closed - no update so far!
Presenter
Presentation Notes
Implications of BQ scheme in conjunction with respective INNS for stakeholders (Patients, regulators, healthcare providers, health care funders, HTA authorities) FDA inviting comments on benefits and challenges of a devoid of meaning v’s meaningful suffix. Also whether BQ should be unique to each biological product v’s each licensee holder Inviting comments on impact of WHO proposal on FDA guidance
Biological Medicinal Products – sales and patent expiry
9.1
7.7
7.5
7.1
6.2
5.6
5.4
5.4
5.1
4.7
4.2
4.2
0 1 2 3 4 5 6 7 8 9 10
Adalimumab (Humira)
Etanercept (Enbrel)
Infliximab (Remicade)
Insulin Glargine (Lantus)
Rituximab (Mabthera)
Bevacizumab (Avastin)
Insulin Aspart (Novomix, Novorapid)
Interferon Beta-1A (Avonex, Rebif)
Trastuzumab (Herceptin)
Glatiramer Acetate (Copaxone)
Pegfilgrastim (Neulasta)
Ranibizumab (Lucentis)
USD$ billion
USD$ billion
EU Expiry date
2016
2017
Expired
Expired
Expired
Expired
2019
Expired
Expired
Expired
Expired
2018
Slide by Peter Richardson, EMA, EBG Conference London 2016
Biosimilars in the pipeline
Presenter
Presentation Notes
According to recent IMS reports about 50 distinct biosimilars are in development and of these 41 are for 4 key biological medicines
Regulatory Science Ireland: Biosimilar Research Project
RSI: Biosimilar Project• Research activities: HPRA and UCC• Objectives
– Peer reviewed scientific publications (practical considerations for HCPs)– Survey perspectives and understanding of biosimilars– Comparative studies of international models for providing safe and
effective use of biosimilars– Develop training activities and online resources– Outreach activities
• Publications to date– Biosimilar Medicines: Opportunities and Challenges in the clinical use and
supply of Biosimilars– Biosimilar Medicines: Recent Developments
