Biosimilars China Guideline. Dr Dr Michel Mikhail

Transcription

1 Biosimilars China Guideline Dr Dr Michel Mikhail 1

2 Contents Regulatory context of biologicals in China Decree 28 issued by SFDA October 2007 Proposed biosimilars guideline 10/29/14 Reference drugs to use Non-Clinical Comparability Studies: in-vitro Non-Clinical pk/pd Studies: in-vivo Immunogenicity and toxicity testing: animals 2

3 Contents (Contd.) Extrapolation and Pharmacovigilance pk/pd clinical studies: in-vivo patients, equivalence design Immunogenicity testing: patients

4 Regulatory Context of Biologics in China Regulatory environment: there are two mandatory requirements to register an imported drug product or biological in Asia Local clinical data needed eg including China in Multicenter Trials Minimal number of Chinese patients in trials is defined in the regulation Need foreign Certificate of an approved Pharmaceutical Product (CPP) at the time of NDA submission (same as for LATAM) 4

5 Regulatory Context of Biologics in China (2) There are different pathways and/or data requirements for imported drugs vs. locally manufactured drugs, chemical vs. therapeutic biologics Imported product: Clinical trial application (CTA) can be filed once the drug enters phase II outside China Local product: CPP is not needed, but the regulatory pathway is designed for a China-only development. CTA can only be filed once manufacturing transfer is done. 5

6 Regulatory Context of Biologics in China (3) Main challenges Timelines are long: CTA review months Limited guidance during development due to SFDA lack of resources & expertise Extensive quality dataset is requested early in development 6

7 Decree 28 issued by SFDA in October 2007 Technical and dossier requirements Annex 3, SFDA Decree 28, for the regulatory requirement of biologics Centre of Drug Evaluation (CDE) issued 27 technical guidances for biologics IND dossier is NDA-like CMC is required API and finished dose manufacturing process, process control and process validation report 7

8 Decree 28 issued by SFDA in October 2007 Describe cell bank, analytical procedures Conduct QC verification for biological products, as part of the CMC review

9 Types of Biologicals which Require Phase I/II/III Trials Biological products not yet marketed overseas or in China mabs Gene therapy, somatic cell therapy Allergen products. Multi component products having extracted or fermented bioactivity from human and/or animal tissues and/or body fluid 9

10 Types of Biologicals which Require Phase I/II/III Trials (2) New combination product made from the already marketed biological products. Imported product approved overseas Strains used for unapproved micro-ecological products

11 Types of Biologicals which Require Phase I/II/III Trials (3) Products without the same structure of an already marketed product, not yet marketed in China or overseas (including amino acid locus mutation, which absence or modification is caused by a different expression system, deletion, changes or chemical modifications of the product). Products manufactured differently from the already marketed product such as use of different expression system or host cell. Products made for the first time with r-dna technology such as use of r- DNA technology to replace chemical synthesis, tissue extraction or fermentation technology Products changed from non-injection to injection, or topical to systemic use, and not yet marketed domestically or overseas. 11

12 Types of Biologicals which Require Only Phase III Trials The marketed products with a change in dosage form but no change in route of administration. Products with a change in route of administration (excluding the previous list). Biological products (Biosimilars) of SFDAapproved biological products 12

13 Biosimilars 29 October 2014 Guidelines for R&D and Evaluation Techniques of Biosimilars Draft Guideline published by Center for Drug Evaluation (CDE), SFDA on October 29, 2014 Final Guideline published by Center for Drug Evaluation (CDE), SFDA in May 2015 in Chinese language only. 13

14 Biosimilars Introduction: China was actively involved as WHO Member in the Development of the WHO Biosimilars Guidelines It was expected that China simply adopts the WHO Biosimilars Guideline rather than developing their own Guideline However China Published the draft of their own Biosimilars Guideline on 29 October

15 Reference drugs to use Originator products registered in China with the State Drug Administration with established safety and efficacy = Reference Listed Biologics (RLBs) As initially mentioned in the Draft Guideline, the RLBs used in different stages of R&D to the greatest possible extent shall be products from the same batch (!) This was removed in the Final Guideline. RLBs not commercially available in China may be acquired through appropriate ways and comply to other national regulations 15

16 Commentary: China s RLB Less strict than Canada; but using RLB from same batch for all R&D is unreasonable and won t capture drift. Also is this logistically feasible? After having received many comments on this issue, the SFDA has deleted this requirement from the Final Guideline published in May

17 Non-Clinical Comparability (NCC) Studies: in-vitro In NCC in-vitro studies, if little or no differences are found, some subsequent comparability tests may be exempted At least three batches shall be used to determine in-vitro comparability The manufacturing process of the biosimilar shall be designed to the RLB s critical quality attributes and be identical in the sequence of process steps 17

18 Determine significant function differences between 18 the biosimilar and the RLB Non-Clinical Comparability Studies: in-vitro (2) Physicochemical properties Primary and higher order structure differences Translational modification differences to N-terminal and C-terminal Amino Acid sequence Glycosylation modification to structure and glycoform of the sugar chains Biological activity

19 Non-Clinical Comparability Studies: in-vitro (3) Purity and Impurity Hydrophobicity, electric charge, molecular size variants, translational modification (including glycosylation) Impurity level differences: processes and host cells Immunological properties of mabs Comparability of Fab and Fc including Q1/Q2 of the affinity, CDC/ADCC activity with antigens and receptors such as FcRn, Fcɣ and ClQ. 19

20 The variable region (Fab) Function: to accommodate the diverse antigen-binding specificities The antigen-binding site is formed by the inter-twining of the light chain variable domain (VL) and the heavy chain variable domain (VH). Each V domain contains 3 short stretches of peptide Complementarity Determining Regions (CDRs) the prominent determinants of antigen-binding affinity and specificity 20

21 The constant region (Fc) The heavy chain contains 3 constant domains: CH1, CH2, and CH3. CH2 and CH3 domains : interactions of the IgG molecule with various components of the immune system binding C1q activates the complement cascade & elicits Complement-Dependent Cytotoxicity (CDC) binding to Fcγ receptors elicits Antibody-Dependent Cellular Cytotoxicity (ADCC). 21

22 Structure and functions of monoclonal antibodies CDR VH VL Antigen- Binding domain Light chain Fab Effector domain C1Q binding site Heavy chain FcRn binding site Fc FcgR binding site FcgR receptor 22

23 Structure and functions of monoclonal antibodies The Fab and Fc portions have 2 different functions. - Fab (particularly in the variable and hypervariable regions) is responsible for Antigen Binding, therefore called Antigen-Binding Domain. - The Fc portion also known as the Effector domain, is responsible for the complement fixation and interaction with the Fc receptors. 23

24 Non-Clinical Comparability Studies: in-vitro (3) Purity and Impurity Hydrophobicity, electric charge, molecular size variants, translational modification (including glycosylation) Impurity level differences: processes and host cells Immunological properties of mabs Comparability of Fab and Fc including Q1/Q2 of the affinity, CDC/ADCC activity with antigens and receptors such as FcRn, Fcɣ and ClQ. 24

25 Commentary: China s NCC invitro Very abbreviated, lacks focus on biosimilarity, but aligned with WHO guideline 25

26 Non-Clinical pk/pd Studies: invivo on animals pk studies on relevant animal species in multiple dose groups on the basis of a single dose or a repeated dose PD studies on relevant animal species Immunogenicity Antibody detection includes screening, confirmation, qualification and correlation with dose and time. If necessary, the cross reaction of the Abs produced shall be determined Evaluate the effect of the quantification comparability results on pk 26

27 Repeated dose toxicity If step-wise approach and similarity is ok, then no need for toxicity studies For studies requiring comparability for efficacy, pk and Immunogenicity, if the results indicate differences related to safety, a toxicity comparability test must be performed One 4-week study on one relevant animal species with the duration long enough to monitor the toxicity or immunoreaction focused on PD 27

28 Commentary on China s NC invivo EU will phase-out all animal testing because it is uninformative, irrelevant and unnecessary 3 R = reduce, replace, refine in the revised EMA Guideline 28

29 pk/pd Clinical studies: in-vivo patients, equivalence design Biosimilar and RLB used for clinical studies shall use the same lot number used in NC in-vitro and in-vivo studies as much as possible. This requirement has been waived now in the final guideline. pk: healthy volunteers and patients acceptable Short half-life and low Immunogenicity use Cross-Over(XO) Design Long half-life or drug-resistant Antibodies use parallel Design Equivalence design % PD clinical studies: clinical study in most sensitive patient population 29

30 Commentary on China pk/pd Human Studies Use of biosimilar and RLB same lot number is impossible, logistically Batch size, Shelf-life, cool-chain, duration of studies, etc. This requirement of same Batch has now been removed from the final guideline Thanks God. 30

31 Immunogenicity testing: patients Comparability study designed according to the result on non-clinical immunogenicity Implemented in the pk/pd comparability study in most sensitive patient population Antibody impurities related to the process must be detected 31

32 Commentary on China s Immunogenicity testing: patients Silent on the duration of testing required presubmission (EU is one year, however you can submit with 6 Months data and submit the 12 Months during evaluation) 32

33 Extrapolation of Indications and Pharmacovigilance Indications with same Mode of Action (MOA) and/or receptor can be extrapolated, provided safety and Immunogenicity of extrapolated indications are fully evaluated in a study Pharmacovigilance and post-marketing risk management plan (RPM) shall be developed in accordance with state regulations, including safety and Immunogenicity evaluation 33

34 Commentary on China extrapolation This is good news! Clinical Study in most sensitive patient population allows extrapolation if same MOA Silent on what type of study (in-vitro or in-vivo on patients) would allow extrapolation. Leaves room for interpretation! 34

35 Commentary on China Pharmacovigilance Same as WHO guideline 35

36 Approval Time Comparison for a Clinical Trial Application (CTA) China: months Only 120 reviewers Plus extra testing required for biologicals by the National Institute for the Control of Pharmaceutical & Biological Products EMA: 2-3 months 4,000 reviewers including external experts USA: 1-2 months 2,000 reviewers 36

37 Positive Impacts and Challenges of the Biosimilars Guideline Positive Impacts: A historical change that provides a relative clear regulatory pathway for biosimilar development in China that helps to: Clarify some confusions Provide principles of R&D and evaluation Help regulate activities and speed-up the entire process

38 Positive Impacts and Challenges Raise the bar for entry into biosimilars field, avoiding malignant competition Similar standards and principles as guidelines from other major markets Increase quality of products Increase competitiveness of products Increase possibility of marketing biosimilars in other countries outside China

39 Positive Impacts and Challenges Challenges: Significantly increase R&D cost Availability of reference product for clinical trials reference product for clinical trials, should be approved in China Basically impossible to obtain a waiver of Phase III comparative trials

40 Positive Impacts and Challenges Extrapolation of indications only limited to indications approved in China Guidelines are too general and impractical Some requirements are too stringent For products not suitable to be developed as biosimilars, could they be developed in accordance with current Drug Registration Regulation?

41 CONCLUSION and Take Home Messages (1) China s Biosimilars Guideline is similar to the WHO Guideline in many aspects The development has to consider doing study(ies) in China The Clinical Trial Application takes Months Conducting the study in China will necessitate excellent planing and will be time consuming 41

42 CONCLUSION and Take Home Messages (2) Following China s biosimilars Draft guideline, would have proven similarity in a specific point in time because of the requirement in using the same lot for the RLB throughout development and clinical trials. This would not have covered the RLBs batch-to-batch variability and the real-life situation for the patient on RLB to switch on the Biosimilar Therefore originators can easily persuade physicians that the biosimilar product does not account for the many process changes (e.g. 21 for Humira alone) 42

43 CONCLUSION and Take Home Messages (3) The Guideline allows Extrapolation of indications and has same Pharmacovigilance requirements as WHO Guideline The China Guidleline is silent on Interchangeability / Substitution, contrary to the US FDA Guideline which requires a separate application (Switching Study?) to grant the status Interchangeable 43

44 Thank you Very Much 44