Biosimilars. Their regulatory status and their use

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Biosimilars Their regulatory status and their use Bruno Flamion, MD, PhD Professor of Physiology & Pharmacology, University of Namur, Belgium Past

1 Biosimilars Their regulatory status and their use 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 History of biological products (or biologics ) 1890 serum therapy (von Behring) 1921 discovery of insulin (Banting & Best) 1983 Humulin, first recombinant drug (Genentech/Eli Lilly) 1986 muromomab, first (murine) monoclonal Ab 1989 epoietin alpha (Epogen ), first therapeutic glycoprotein (Amgen) 1994 abciximab, first chimeric monoclonal Ab 1996 daclizumab, first humanized monoclonal Ab 1997 rituximab (Mabthera ); 1998 trastuzumab (Herceptin ); 1999 infliximab (Remicade ) 2002 adalimumab (Humira ), first human monoclonal Ab 2004 bevacizumab (Avastin ), cetuximab (Erbitux ) 2

4 Definition of a biosimilar 1. = a copy of a biologic (which cannot be exactly the same for biological reasons) but not a simple copy ( intended copy ). 2. The biosimilar copy must have successfully completed a comparability exercise vs the originator ( the reference product ). 3. During that exercise the biosimilar must pass a number of qualifications, assays, non-clinical tests, and also (at least in the EU) clinical tests. 4. This exercise must meet strict regulatory requirements, for instance those set up by the European Medicines Agency (EMA) or, more recently, the FDA 5. The goal is to ensure that using the biosimilar instead of the reference product entails a very low (negligible) likelihood of clinically significant difference. 4

5 Regulations vary across the world EMA-like regulation «Simple copy» or generic regulation No regulation European Union (EMA) since 2005 Mexico China * USA (FDA) since 2012 Peru Russia WHO since 2009 Canada Australia Japan South Korea, Taiwan South Africa, Jordan Turkey, Brazil (new) Chile India * Out of 382 biologics on the market in China, 361 are simple copies 5

6 Economic push: EPO price competition in Germany 6

7 Economic push: use of filgrastim in Europe 7

8 Variable uptake of biosimilar G-CSF in Europe

How to make a similar biological product?

process that makes them difficult to copy;

as the originator Cloning into DNA vector

Ann Rheum Dis. 2013;72(3):322-328. Ahmed I.

9 How to make a similar biological product? Biologics have a complex manufacturing process that makes them difficult to copy; the end product is not to exactly the same as the originator Cloning into DNA vector Coding gene mutation Transfer into host cell expression Different purification and formulation protocols Dörner T, et al. Ann Rheum Dis. 2013;72(3): Ahmed I. Clinical Therapeutics 2012; 34(2): Different cell culture processes

The size matters A political decision was made in 2004 to allow official copies of existing biological products based on a reduced dossier in parallel with the generic concept taking advantage of

10 The size matters A political decision was made in 2004 to allow official copies of existing biological products based on a reduced dossier in parallel with the generic concept taking advantage of experience with the comparability of biotech products after a change in manufacturing process The goal was (is) purely pharmaco-economical There is no official definition of a biosimilar in the EU From Joerg Windisch, CSO Sandoz 10

in terms of potency, half-life and immunogenicity Rudd,

11 but also the intrinsic heterogeneity (e.g. glycoforms) Biologicals are micro-heterogeneous mixtures of several isoforms, each of which may differ in terms of potency, half-life and immunogenicity Rudd, P. M., et al. (1997) The glycosylation of the complement regulatory protein, human erythrocytes CD59. J. Biol. Chem. 272:

12 Example of biological product complexity pyro-e D O O G D D O G O pyro-e D Pyro-Glu (2) Deamidation (3 x 2) Methionine oxidation (2 x 2) D D Glycation (2 x 2) G G High mannose, G0, G1, G2 (5) K K (9600) potential variants Sialylation (5) C-term Lys (2) 2 x 6 x 4 x 4 x 5 x 5 x 2 = 9600 Modified from: Koszlowski, S. & Swann, P. (2006) Adv. Drug Delivery Revs. 58,

13 EMA requirements for biosimilar approvals *** *** Including receptor binding assays (affinity, reversibility), epitope analysis (for a MAb), bioassays )

14 The comparability exercise (ICH, 2004) 14

15 Comparability Exercise for existing products Number of manufacturing changes approved for mabs/-cepts in rheumatology The latest versions of Remicade are «biosimilars» of the previous versions From Schneider CK et al., Ann Rheum Dis 2013; 72:315 Physicochemical characteristics of subsequent products do not have to be identical but «highly similar» (they may be slightly improved) 15

16 Comparability Exercise vs Biosimilarity Comparability (change in manufacturing process) Thorough internal knowledge by manufacturer Extensive analytical data Low need for clinical data Biosimilarity No internal knowledge Extensive analytical data High need for clinical data Noninferiority tests Therapeutic equivalence If the comparison fails at any stage, the products cannot be declared biosimilar 16

17 EMA guidelines for biosimilar development 17

18 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) CT Arzneimittel 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

19 Biosimilars at the European Medicines Agency (2) Identical products MAb In all indications!! Remsima (infliximab) Celltrion Authorized 20 Inflectra (infliximab) Hospira Authorized 8 ** 21 Ovaleap (follitropin alpha) Teva Authorized 22 Gastrofil (filgrastim) Apotex Authorized Bemfola (follitropin alpha) Finox Biotech AG Authorized Abasaglar (insulin glargine) Lilly-Boehringer Authorized 12 NB. At FDA: Basaglar (not a biosimilar 505(b) procedure Biosimilars under evaluation 1 insulin at EMA NB. Celltrion s trastuzumab approved in S. Korea (January 2014) 7 Jan 2014: FDA Oncology Advisory Committee supported Zarxio as biosimilar ** Marketed in Norway, Portugal, Ireland, Finland, Eastern Europe; pending patent issues in other EU States FDA-approved

FDA Guidance (2012) and issues Q/S/E stepwise approach (like EU); decision based on the totality of evidence The extent of clinical study required depends on remaining uncertainty after in vitro and

20 FDA Guidance (2012) and issues Q/S/E stepwise approach (like EU); decision based on the totality of evidence The extent of clinical study required depends on remaining uncertainty after in vitro and animal testing (some biosimilars could be approved without a need for clinical trials) FDA is obliged to rule also on the interchangeability of each biosimilar (yes or no): product expected to produce the same clinical outcome as the reference product in any given patient The biosimilar company has to reveal the details of its manufacturing methods to the originator Will FDA use the same INN? NB. FDA accepted the Remsima biosimilar application in August

21 Why is there (still) a debate on biosimilars?

22 The biosimilar concept is purely pharmacoeconomic Without a reduction in regulatory requirements, this concept is not tenable How can regulatory requirements be reduced without undue risks (unacceptable loss of efficacy, or unexpected immunogenicity)? 22

23 Methods agreed by regulators to ensure efficacy and safety of biosimilars with less patients than originator 1. At least one accurate PK study (if possible, PK/PD data) 2. Less patients but enough statistical power to detect differences if they exist: more homogeneous population * in principle, the most sensitive endpoints * reasonable equivalence margins ( leads to some additional uncertainty) 3. Extrapolation of indications if the mechanism of action, safety and immunogenicity are expected to be similar in these indications 4. Reinforced Risk Management Plan (RMP) * For anti-tnf, RA is a sensitive population (perhaps more sensitive than IBD or psoriasis) * In oncology, it is preferable to use early stage cancer patients and a «response rate» endpoint rather than survival rates 23

24 Response Rate, % Results of CT-P13 (infliximab) Phase III equivalence trial N= 606. Primary efficacy endpoint: ACR20 response at week Treatment difference = 2% (95% CI: 6%, 10%) Treatment difference = 4% (95% CI: -4%, 12%) 184/ / / /251 ITT Population PP Population CT-P13 INX 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):

25 Evolution of Remicade (EU): Efficacy RA: joint damage Fistulizing CD maintenance Moderate/ Severe Psoriasis Crohn s Disease Ankylosing Spondylitis Psoriatic Arthritis RA: signs and symptoms RA: physical function Luminal CD maintenance Early RA Ulcerative Colitis Basis for extrapolation of indications for Remsima /Inflectra, together with PK data in AS + Post-approval commitment for a Ph III trial in Crohn s disease

26 Biosimilar MAbs in oncology The clinical issues are not different from other biosimilars but extrapolation may be technically more difficult Very complex production Very complex mechanism of action Complex (oncology) indications 26

27 Increased immunogenicity of biosimilars? EMA/CHMP. Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues.

28 Immunogenicity & traceability 1. Immunogenicity in humans cannot be predicted from animal data absolute need for comparative clinical trials including tests for neutralizing Abs and PK/PD data 2. How long? Usually 1 year pre-licensing if chronic use is intended; the post-marketing RMP is crucial thereafter 3. Adequate traceability is mandatory. The recommendation is to identify the product (in case of, e.g., hypersensitivity) by INN + brand name + manufacturer + batch number (+ country of origin) NB. Some complain that the SmPC of the biosimilar is identical to that of the originator (except a simple mention in 5.1: «X is a biosimilar detailed information available on website of EMA».) 28

29 Interchangeability 1. Can a patient be switched from an originator to a biosimilar during (chronic) treatment? and vice-versa 2. Studies designed to demonstrate that switching (back and forth) does not entail any additional risk would be long, costly and probably unreasonable (cf. ongoing issue at FDA) 29

30 Recent initiative towards interchangeability NOR-SWITCH study 800 patients started recruiting in November 2014

31 Interchangeability 1. Can a patient be switched from an originator to a biosimilar during (chronic) treatment? and vice-versa 2. Studies designed to demonstrate that switching (back and forth) does not entail any additional risk would be long, costly and probably unreasonable (cf. ongoing issue at FDA) 3. In Europe, demonstrated biosimilarity would imply interchangeability but the decision is up to each Member State. 4. In Belgium, FAMHP excludes biologics from INN prescription and forbids automatic substitution of biologics by pharmacists 31

32 Some Take-Home Messages

33 Take-home messages (1) 1. The biosimilarity concept means a low likelihood of clinically significant differences 2. According to (EU, FDA ) regulators, a product can be called biosimilar only if it has successfully gone through the stepwise (Q/S/E) comparability exercise (i.e., strong regulatory oversight) and is thus considered of high quality, safe, and efficient

34 Take-home messages (2) 3. The focus of the clinical part of the biosimilar exercise is on PK/PD and the use of sensitive populations and endpoints to detect any potential difference 4. Extrapolation of indications is key to the biosimilar concept but needs to be justified in all cases and explained to clinicians!

35 Take-home messages (3) 5. Detection of immunogenicity and a good Risk Management Plan are key elements of safety so far there has been no safety issue with any biosimilar product 6. Traceability should be ensured by prescribing under brand names and keeping good records 7. Interchangeability is a national (or local) issue in most of Europe, automatic substitution by pharmacists is not allowed involving the prescriber is preferable

36 Take-home messages (4) 8.Clinicians, supported by national and local (hospital) decision makers, could give away some prescription habits in favour of lower prices 9.Infliximab biosimilars, impacting on well-defined medical specialties (rheumatologists, gastroenterologists, dermatologists) and high cost situations, will be a good test

37 Thank You!!

How are biosimilars assessed and approved?

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