Biosimilar regulation from a clinical point of view

Transcription

1 Biosimilar regulation from a clinical point of view an update on immunogenicity and interchangeability LIS-TNFBio seminar 2018 Scandic Nidelven Hotel Trondheim mars Senior Advisor Project leader Biosimilars / Clinical Assessor Member of the CHMP - Biosimilar Working Party European Medicines Agency, London venke.skibeli@noma.no

2 Topics o European regulation of biosimilars o What are biosimilars? Regulatory aspects Immunogenicity of biologicals o Regulatory challenges Interchangeability Traceability 2 Edvard Munch, The sick child, 1896

3 Disclaimer The views expressed in this review are the personal views of VS and should not be understood or quoted as being made on behalf of or reflecting the position of the European Medicines Agency or one of its committees or working parties. 3

4 Biosimilars in the EU The EU has the highest number of biosimilar medicines approved, and extensive experience of their use and safety; The EU s legal framework on biosimilars has been in place since 2004 and is used by other international regulators; Over the last 12 years, the EU monitoring system for safety concerns has not identified any relevant difference in the nature, severity or frequency of adverse effects between biosimilar medicines and their reference medicines. 4

5 Biologicals Purified blood products Advanced therapies Recombinant proteins Heparin- enoxaparin sodium Insulin Therapeutic proteins - Present basis for development og biologicals Vaccines 5 Enzymes Insulin

6 Biologicals are BIG! drug IgG Protein molecules are flexible, unstable and sensitive with regards to heat, ph, ion strength, oxidation, light Peptides may also be synthesized chemically = no biological Heparin biological in the EU / regulated as a synthetic drug in the US/FDA 6

7 Monoclonal antibody MoAb structure SS IgG immune globulin 7

8 Batch variability Non-identicality is a normal principle in biotechnology No batch of any biological is identical to the others The art is to demonstrate that the biosimilar is as close as possible to its reference product in all relevant functional and structural aspects, 8

9 What is a biosimilar? From EMA - revised general guideline 2015: A biosimilar is a biological medicinal product that contains a version of the active substance of an already authorised original biological medicinal product (reference medicinal product). A biosimilar demonstrates similarity to the reference medicinal product in terms of quality characteristics, biological activity, safety and efficacy based on a comprehensive comparability exercise. 9

10 Can biosimilars be developed to any biological product? In principle, the concept of biosimilarity is applicable to any biological medicinal product. The success of developing a biosimilar will depend on the ability to produce a medicinal product which is similar to the reference medicinal product, and to convincingly demonstrate the similar nature of the concerned products

11 11 The Comparability Exercise A technical expression Shows that two biologicals are similar 1) Scenario 1: Change in the manufacturing process ( pre- and post-change product from the same manufacturer) 1) Scenario 2: A biosimilar is launced (compared to the reference)

12 Biosimilar epoetin-alpha (authorised in Europe) Brockmeyer and Seidel, EJHP

13 Risk of failure decreases Biosimilarity general aspects Development and conclusion on biosimilarity is a step-wise approach 1. Step: quality level, to establish high similarity in a comprehensive comparability exercise 2. Step: non-clinical level, great importance of functional assays to substantiate similar effects 3. Step: clinical level, lower sensitivity for demonstration of similarity, comparison should confirm biosimilarity as observed above If not, can it be explained (why, how)? What additional data can minimise concerns?

14 Biosimilarity is based on the totality of evidence Originator study Biosimilar study Demonstration of biosimilarity follows the principles of comparability testing (ICH Q5E) for pre- and post-change manufacturing process Physiochemical and functional assays are the most sensitive to reveal subtle differences Source: Cleveland clinic 14

15 Basic principle for clinical development of biosimilars The aim of a biosimilar development programme is not to establish benefit of a treatment for the patient this has been done before for the reference product! The aim is to establish biosimilarity! The art is to demonstrate that the biosimilar is as close as possible to its reference product in all relevant functional and structural aspects, within current technical and scientific limitations (inherent variability). 15

16 Basic principles for clinical development of biosimilars This means: The clinical study follows the idea that patients are models The clinical study is selected to represent the most sensitive model to study differences Thus, trial design might be (entirely) different from the normal guideline principles! Scientifically not abridged, but rather tailored development For interchangeability, this means: Specific data currently not requested in the EU, since development focuses on comparability exercise itself But close similarity supports switching 16

17 Tailored clinical programme Demonstration of similarity, not patient benefit per se PK studies mandatory and preferably in healthy subjects Endpoints in clinical trials should be sensitive and study population homogeneous to detect potential drug-related differences in pharmacological effects Clear shift to PD endpoints Glucose infusion rate (in clamp studies) for insulin Anti FXa and anti FIIa activity for LMWH Absolute neutrophil count (ANC) for G-CSF Number of oocytes retrieved for follitropin (IVF) 17

18 Evolution of Biosimilars in the EU Guidance Overarching guideline Quality guideline Non-clinical/Clinical guideline mab guideline, revision of overarching and general guidelines Product-specific guidelines (new GLs and revisions) First biosimilar somatropin First biosimilar eopoetin First biosimilar filgrastim First biosimilar mab (infliximab) and follitropin alfa Product authorisation First biosimilar insulin glargine First biosimilar etanercept and enoxaparin sodium First biosimilar teriparatide, rituximab and adalimumab FDA (US) approved their first biosimilar in 2015

19 Biosimilar reviews are not abridged or accelerated Time to positive opinion issued by the European Medicines Agency (days) Schneider CK: Biosimilars in rheumatology: the wind of change. Ann Rheum Dis Mar;72(3): (Data source: EPARs on EMA website) 19

20 Regulators and clinicians have different viewpoints Biosimilar RMP S & E PK Nonclinical tests Analytical comparisons Pharmaceutical documentation Lack of confidence in comparability Reliance on the experience gained from manufacturing changes Confidence in clinical trials Clinical trials as a part of the comparability (totality of evidence) Biosimilar is a new product Biosimilar contains a new version of the active substance of the reference product 20

21 Immunogenicity It is impossible to predict the incidence of unwanted immunogenicity the characteristics of the immune response the clinical consequences and significance of such immunogenicity Immunogenicity of biosimilars is the reference product immunogenic? Impossible to predict an increase or decrease The Applicant has to include immunogenicity data when submitting the dossier Monoclonal Ab Growth hormone insulin 21

22 European guidance for immunogenicity of therapeutic proteins 1 Immunogenicity assessment of therapeutic proteins EMEA/CHMP/BMWP/14327/2006 Rev. 1 Adopted by CHMP June 2017 Effective from December 2017 Immunogenicity assessment of monoclonal antibodies intended for in vivo clinical use. (EMA/CHMP/BMWP/86289/2010) (2012) jsp&mid=WC0b01ac cb 22

23 Essentials from the new guideline Multidiciplinary Summary of immunogenicity Bringing in all aspects from production to treatment Risk assessment Justification of a risk based approach to immunogenicity needed Assays The basis is the development of adequate screening and confirmatory assays Properly validated assays: Incidence of ADAs? Look for neutralisation/persistence Clinical correlation integrated analysis of immunological, PK, PD, clinical efficacy and safety data clinical consequences impact on PK, safety, efficacy 23

24 Immunogenicity of biosimilar infliximab Source: EPAR Remicade; PLANETRA study (Yoo DH, et al. Ann Rheum Dis Oct;72(10): Christian Schneider 24

25 A risk based approach to immunogenicity Production of ADAs? What methods has been used? Validation of assays? Are the ADAs neutralising? Further characterisation of ADAs Infusion-related reactions/ hypersensitivity Clinical correlation of ADA production PK measurements Clinical consequences Efficacy & safety 25 High risk - epoetin Low risk - alemtuzumab

26 Interchangeability, switching and substitution* Interchangeability refers to the possibility of exchanging one medicine for another medicine that is expected to have the same clinical effect. This could mean replacing a reference product with a biosimilar (or vice versa) or replacing one biosimilar with another. Replacement can be done by: Switching, which is when the prescriber decides to exchange one medicine for another medicine with the same therapeutic intent. Substitution (automatic), which is the practice of dispensing one medicine instead of another equivalent and interchangeable medicine at pharmacy level without consulting the prescriber. *) Definitions according to EMA/EC Information guidance for HCP from May

27 Switching of biologicals Immunogenicity is a frequently mentioned concern of switching to biosimilars Not much evidence for these concerns (Kurki et al, 2017; Cohen et al, 2018, Mckinnon et al., 2018) Mostly switching studies have been performed, alternating studies are rare Alternating studies may increase following US guidance. (Draft guidance on interchangeability, January 2017) It all comes down to traceability Rogers (2006), Nephrology (Carlton) 11(4):341-6; Mellstedt et al (2008), Ann Oncol19(3):411-9; Barosi et al (2011), Haematologica 96(7):937-42; Scheinberg and Kay (2012), Nat Rev Rheumatol. 8(7):430-6; Gecse et al (2013), Gut 62(6):803-7

28 Norwegian Medicines Agency position on interchangeability 28

29 29 Biosimilar-meeting in the EU- Commission, May 5 th 2017 Hans Ebbers (Project Leader of the Pharmacotherapeutic Group III at the Medicines Evaluation Board (MEB/CBG) in The Netherlands): According to Ebbers: Thus far there is no evidence that switching to/from biosimilars causes safety issues (Ebbers et al, 2012; Kurki et al, 2017) Differences in efficacy/safety may be hard to establish Hard to draw definitive conclusions from switching studies, other than a general reassurance that no problems have occurred as a result from the switch If the key concern is immunogenicity, then anti-drug antibodies (ADAs) in relation to clinical outcomes or trough levels should be determined

30 Recent publication with EU colleagues Conclusion: Biosimilars in the EU are interchangeable

31 31 Biosimilars in the EU : Where are We Now? o More than 10 years of experience with biosimilars confirm their safe and effective use and support the scientific approach taken o Rapid advances in the analytical sciences allow comprehensive characterisation of increasingly complex molecules (e.g. mabs) If biosimilarity has not been shown at the quality level this cannot be overcome by clinical trials. o Risk-based approach for in-vivo animal studies o Since both EMA and FDA accept the use of a global reference product in clinical studies (if a proper bridge has been established), sponsors are striving for global development of their biosimilars

32 Expected benefits of biosimilars Biosimilars introduce competition on the market Tailored development programmes reduce development costs Nevertheless, pharmaceutical quality, efficacy and safety (including immunogenicity) expected to be highly similar to reference product Increase in patient access to valuable and modern treatment options and containment of health care costs From the EMA perspective: Biosimilars approved in the EU are of good quality, are efficacious and safe in use! 32

33 Thank you! Follow legemiddelverket legemiddelverket.no

34