How are biosimilars assessed and approved?

Transcription

1 How are biosimilars assessed and approved? Bruno Flamion, MD, PhD Professor of Physiology & Pharmacology, University of Namur, Belgium Past Chair of the European Medicines Agency (EMA) Scientific Advice Group Past Chair of the Committee for Reimbursement of Medicines in Belgium (CTG/CRM)

2 What is a biosimilar? A new product that is similar to an originator product The biosimilar (like generics) can only be approved once the patent and data protection of the originator have expired (usually, 12 years after marketing authorisation) The originator must be a (synonyms): biological medicinal product (EMA) biotherapeutic product (WHO) biologic (FDA) biological However, the biosimilar cannot be a simple copy It must pass a series of strict comparative tests vs one particular originator, selected as the reference product 3

3 Difficulties linked to biological products 1. Cannot be synthesized chemically require a living organism or cell culture 2. Complex manufacturing process 3. Intrinsic variability (e.g. glycoforms) 4. Variability between production lots / batches 5. Changes in manufacturing process may occur and are tightly controlled by regulatory authorities (need for comparability exercise ICH Q5E) 6. Can generate immune responses 7. Require a strict Risk Management Plan (surveillance) Creating a biosimilar is difficult and costly 3

4 Main biologics 1921 discovery of insulin (Banting & Best) 1983 first recombinant human insulin (Humulin ) 1985 first recombinant human growth hormone 1989 epoetin- (first recombinant glycoprotein) 1991 filgrastim (granulocyte-colony stimulating factor) 1997 rituximab (first non-murine monoclonal antibody) (MabThera ) >1998 trastuzumab (Herceptin ), = replacement therapies infliximab (Remicade ), etanercept (Enbrel ), adalimumab (Humira ), insulin glargine (Lantus ), = available as biosimilars today 4

5 Generics vs biosimilars: different concepts (1) Generic Reference is a small, chemically synthesized molecule. Biosimilar Reference is a biological product aspirin monoclonal AB 6

6 Generics vs biosimilars: different concepts (2) Generic Reference is a small, chemically synthesized molecule. Is identical with regard to qualitative and quantitative composition in active substances; has the same pharmaceutical form as the reference. Bioequivalence with the reference product has been demonstrated through appropriate bioavailability studies Biosimilar Reference is a biological product. Is similar in terms of quality, safety and efficacy to an already licensed and extensively characterized reference. Cannot be identical due to biologic variability Bioequivalence with the reference is only one part of a full comparative exercise The exercise must meet the WHO, EMA or FDA guideline requirements

7 The same cell always produces different glycoforms 1 Biologics: intrinsic heterogeneity Complex biologics (like MAbs) are always micro-heterogeneous mixtures of several isoforms, each of which may differ in terms of potency, half-life and immunogenicity 2 1. Rudd, P. M., et al. J. Biol. Chem. 1997;272: FDA. Scientific Considerations in Demonstrating Biosimilarity to a Reference Product

8 All lots of the original product are not identical 1500 Biological activity (U/µg) Acceptable variability for the company, EMA & FDA Year 1 Year 2 Year 3 Year 4.. Theoretical example EMA: European Medicines Agency FDA: Food & Drug Administration (USA) 8

9 Biologics: complex manufacturing process Cloning into DNA vector Coding gene mutation Transfer into host cell expression Different cell culture processes Different purification and formulation protocols The process is difficult (but not impossible) to reproduce closely Dörner T, et al. Ann Rheum Dis. 2013;72(3): Ahmed I. Clinical Therapeutics 2012; 34(2):

10 5 comparative steps required to approve a biosimilar 1. technical qualifications 2. bioassays (for instance, on human cells) 3. non-clinical tests in animals 4. at least 2 clinical trials in humans: one PK/PD, one Phase III trial in the most sensitive population with sensitive endpoints (i.e. able to detect a difference if there is one) 5. specific post-marketing surveillance ( Risk Management Plan ), e.g. check for unexpected immunogenicity This is called by the EMA a full comparability exercise (although this term officially refers to the Comparability of Biological Products Subject to Changes in Their Manufacturing Process Q5E ICH document) The FDA talks about a stepwise comparative exercise 9

11 Biosimilars at the European Medicines Agency (1) Omnitrope (somatropin) Sandoz (Novartis) Authorized 2 Valtropin (somatropin) [yeast] Biopartners Authorized 3 Alpheon (interferon alfa) BioPartners Negative 4 Binocrit (epoetin alfa) Sandoz (Novartis) Authorized 5 Epoetin alfa Hexal (epoetin alfa) Hexal (Novartis) Authorized 6 Abseamed (epoetin alfa) Medice Authorized 7 Silapo (epoetin zeta) Stada Authorized 8 Retacrit (epoetin zeta) Hospira Authorized 9 Insulin Marvel Short (human insulin) Marvel Life Sci Negative 10 Insulin Marvel Intermediate (human insulin)marvel Life Sci Negative 11 Insulin Marvel Long (human insulin) Marvel Life Sci Negative 12 Filgrastim Ratiopharm (filgrastim) Ratiopharm Authorized 13 Biograstim (filgrastim) AbZ-Pharma GmbH Authorized 14 Tevagrastim (filgrastim) Teva Authorized 15 Zarzio (filgrastim) Sandoz (Novartis) Authorized 16 Filgrastim Hexal Hexal (Novartis) Authorized 17 Biferonex (interferon beta-1a) BioPartners Negative 18 Nivestim (filgrastim) Hospira Authorized 1 2 withdrawn 3 4 These 3 products are identical!! 5 6 7

12 Biosimilars at the European Medicines Agency (2) Identical First MAb In all indications!! products Remsima (infliximab) Celltrion Authorized 20 Inflectra (infliximab) Hospira/Pfizer Authorized 8 21 Ovaleap (follitropin alpha) Teva Authorized 22 Gastrofil (filgrastim) Apotex Authorized Bemfola (follitropin alpha) FinoxBiotech AG Authorized Abasaglar (insulin glargine) Lilly-Boehringer Authorized 12 NB. At FDA: Basaglar 2 (not a biosimilar 505(b)(2) procedure) FDA-approved Some data not developed by the Applicant Benepali (etanercept) Samsung-Bioepis Authorized Flixabi (infliximab) Samsung-Bioepis CHMP app. 14

13 Biosimilars under evaluation at the EMA INN Reference product Month of submission enoxaparin Clexane March 2015 (2 dossiers) rituximab Mabthera November 2015 etanercept Enbrel December 2015 pegfilgrastim Neulasta December 2015 (3 doss.) adalimumab Humira December 2015 (2 doss.) insulin glargine Lantus January 2016 teriparatide Forsteo January 2016 (2 doss.) 13

14 What about the FDA? Have approved follow-on biologics based on regular BLA (biological license application), e.g. Teva s tbo-filgrastrim (equivalent to Tevagrastim in the EU) New (2012) BPCI Act, framework, and guidelines on abbreviated BLA for biosimilars now available FDA approved Sandoz Zarxio (filgrastimsndz) in March 2015 and Celltrion s Inflectra (infliximab-dyyb) on 5 April 2016 FDA could also approve interchangeable products (none so far) to which patients can be switched from an originator (and vice versa) NB. EMA does not rule on interchangeability (and certainly not on automatic substitution) FDA. Scientific Considerations in Demonstrating Biosimilarity to a Reference Product

15 Regulations on biosimilars/copies vary across the world EMA-like biosimilar regulation Europe (EMA) since 2005 WHO since 2009 USA (FDA) since 2012 Canada, Australia Japan, South Korea, Taiwan Saudi Arabia Generics-like regulation ( biocopies ) Mexico, Peru, Chile India (eg. Reditux retuximab by Dr Reddy s; CANMab trastuzumab by Biocon/Mylan; BOW015 infliximab by Ranbaxy ) Regulation inspired from EMA but lower (clinical) requirements South Africa, Jordan Turkey Brazil, Argentina No or unclear regulation Russia China 1. Dorner T, et al. Ann Rheum Dis 2013; 72:

16 Examples of reference vs biosimilar comparative tests and trials 17

17 CT-P13 (infliximab) vs Remicade: ex. of analytical data Secondary structure: FT-IR spectrometry Remicade TM Batch #2 CT-P13 batches Remicade TM Batch #1 Jung SK et al. mabs, 2014;6(5):

18 CT-P13 (infliximab) vs Remicade PK trial in AS patients CT-P13 n= 221 PLANETAS Park W, et al. Ann Rheum Dis 2013; doi: /annrheumdis

19 CT-P13 Phase III equivalence trial in RA patients N= 606. Primary efficacy endpoint: ACR20 response at week 30 Response Rate, % Treatment difference = 2% (95% CI: 6%, 10%) Treatment difference = 4% (95% CI: -4%, 12%) 184/ / / /251 ITT Population PP Population CT-P13 INX PLANETRA Safety: Treatment-emergent adverse events were seen in 35.2% of patients treated with CT-P13 and 35.9% of patients treated with INX Immunogenicity: Equivalent levels of anti-infliximab antibodies were detected in both treatment arms at week 14 and week 30 Yoo DH, et al. Ann Rheum Dis. 2013;72(10):

20 Evolution of Remicade indications in EU + Paediatric indications RA: joint damage Fistulizing CD maintenance Moderate/ Severe Psoriasis Crohn s Disease RA: physical function Ankylosing Spondylitis Psoriatic Arthritis RA: signs and symptoms Luminal CD maintenance Ulcerative Colitis Early RA Basis for extrapolation of indications for Remsima /Inflectra + Post-approval commitment for a Ph III trial in Crohn s disease 21

21 Extrapolation of indications (1) Means that one Phase III clinical trial comparing biosimilar and original can serve as the basis to approve all other indications of the original Is the key concept for biosimilars (only way to decrease the cost of development) Requires that the Phase III trial is carefully selected: the patient population and the endpoints must be the most sensitive to detect a difference if it exists Extrapolation is granted on a case-by-case basis: IF the mechanism of action, safety, and immunogenicity are expected to be similar in these indications (= value judgment by regulators and experts) 22

22 Extrapolation of indications (2) Regulators The goal of a biosimilar development is to demonstrate similarity, not clinical benefit, which was proven for the original product. Clinicians «We need studies proving efficacy and safety of the biosimilar in our indications» More clinical trials will not improve the demonstration of similarity. In vitro assays are usually most sensitive to detect differences in pharmacological activity. Blood. 2014;124(22):

23 Extrapolation of indications (3) Numerous publications by clinicians 23

24 Biosimilar MAbs in oncology The clinical issues are not different from other biosimilars but extrapolation may be technically more difficult Very complex mechanisms of action Complex (oncology) indications 24 Guideline on similar biological medicinal products containing monoclonal antibodies non-clinical and clinical issues. EMA/CHMP/BMWP/403543/2010.

25 Switching patients to biosimilars Interchangeability? Efficacy and safety of switching between reference and biosimilar not fully demonstrated in clinical trials of biosimilars (would mean long and difficult studies) EMA does not rule on interchangeability or switch Can lead to automatic substitution by pharmacists and to lack of traceability May entail some risks, e.g. increased immunogenicity (but this is unproven) Any change in therapy can destabilize a well-treated patient 25

26 Recent initiative towards interchangeability NOR-SWITCH study 2 Target = 500 patients Ended recruiting in June Patients with all indications of Remicade are randomised to blindly stay on drug or switch to Remsima 2 Primary endpoint is occurrence of disease worsening at 52 weeks 2 Several secondary endpoints 1. Stanton D. Norway to facilitate switch to biosimilars with $3m Remicade study. BioPharma, Clinicaltrials.gov. The NOR-SWITCH study. 26

27 Conclusions 27

28 Summary 1. A biosimilar is NOT a biogeneric of the reference biologic, due to intrinsic variability and non-identical production steps. 2. Approving biosimilars is a complex exercise overseen by regulatory authorities such as EMA, FDA, WHO This exercise ensures a very low likelihood of clinically significant differences. 3. The comparative physicochemical characteristics of the biosimilar and the reference product are scrutinized. In vitro assays are most sensitive to detect differences in pharmacological activity. 29

29 Summary 4. One comparative PK study and one therapeutic equivalence study are requested. Extrapolation of indications is key to the biosimilar concept but needs to be justified in all cases (e.g., similar mechanism of action in all indications). 5. Detection of immunogenicity and a good Risk Management Plan (role of pharmacists) are key elements of safety. 6. Traceability should be ensured by prescribing under brand names and keeping good records. Interchangeability is a health policy issue dealt with at national level. 30

30 Belgian biosimilar? La Reproduction Interdite (portrait d Edward James), René Magritte, 1937 Boymans-van Beuningen Museum, Rotterdam Suggested by Prof. Wolgang Jelkmann 30

31 Thank You!! 31