Interchangeability and Substitution for Biological Medicinal Products Regulatory aspects

Transcription

1 Interchangeability and Substitution for Biological Medicinal Products Regulatory aspects Keith Watson, PhD 12th ALIMS Symposium, Kragujevac, ADSBIO160162

2 Guiding Principle Access to safe and effective medicines is important to patients, to those who care for them and to AbbVie AbbVie fully supports the entry of biosimilars that have been shown, with robust evidence, including clinical trials, to be as safe and efficacious to the innovator biologic medicines 2

3 Overview Definitions Regulatory State of Play Demonstrating Interchangeability Why? Demonstrating Interchangeability How? Interchangeability and Substitution in Clinical Practice Summary 3

4 Definitions

5 Definitions Interchangeability : FDA can designate a biosimilar as interchangeable if: 1 Expected to produce the same clinical result as the reference product in any given patient Repeated switching between biosimilar and reference product presents no greater safety or efficacy risk vs the reference product European Commission definition: 2 The medical practice of changing one medicine for another that is expected to achieve the same clinical effect in a given clinical setting and in any patient Conducted on the initiative of, or with the agreement of the prescriber FDA requirements to meet interchangeability threshold are still to be defined In Europe, decisions on interchangeability rely on national competent authorities and are outside the remit of EMA/CHMP Substitution (pharmacist action): Dispensing one medicine instead of another equivalent and interchangeable medicine at the pharmacy level without consulting the prescriber 2 1. FDA Biologics Price Competition and Innovation Act 2009; 2. European Commission. Consensus Information Paper What you need to know about Biosimilar Medicinal Products,

6 Biosimilarity Does Not Imply Interchangeability Small Molecules/Generic Drugs Biologics/Biosimilars = Produced using chemical synthesis 1 Less sensitive to production process change 1 Reproducibility easy to establish 1 Regulatory agencies generally designate the two as interchangeable* Depending on local rules, pharmacists may be authorized or required to substitute a generic for the original without informing the prescribing physician (automatic substitution) Produced by complex biological process in cell lines 1 Requires specialized production facilities 1 Sensitive to production process changes 1 Reproducibility difficult to establish 1 Due to their complexity and impurity profiles, interchangeability could have clinical consequences and repeated switches may increase immunogenicity 2 Biosimilarity status does not imply interchangeability 3 8 *EMA still defer to national agencies 1. Sekhon and Saluja. Biosimilars 2011;1:1 11; 2. Scott et al. J Clin Pharmacol 2015;55:S123 32; 3. Declerck. GaBi J 2012;1:13 6; 4. FDA. Biosimilar Guidance Webinar Biosimilar Biological Products 2012; 5. EMA. Q&A on biosimilar medicines, 2012; 6. MHLW. Guideline for the Quality, Safety, and Efficacy Assurance of Follow-on Biologics, 2009 by PhRMA; 7. FDLI s Food and Drug Policy Forum. 2012;2:1 20; 8. Health Canada. Q&A on Information and Submission Requirements for Subsequent Entry Biologics,

7 Regulatory State of Play

8 US/FDA: Interchangeability/Substitution for Biosimilars Following passage in 2010 of the Biologics Price Competition and Innovation Act, FDA can deem certain biosimilars as interchangeable : Under US law, interchangeable means: The biological product is biosimilar to the reference product It can be expected to produce the same clinical result as the reference product in any given patient For a product administered more than once, the safety and efficacy risks of alternating or switching are not greater than with repeated use of the reference product Substitution is regulated at state level FDA Biologics Price Competition and Innovation Act

9 EU/EMA: Interchangeability/Substitution for Biosimilars (1) The EMA s evaluations do not include recommendations on whether a biosimilar could be used interchangeably with its reference medicine 1 For questions related to switching from one biological medicine to another, patients should speak to their doctor and pharmacist 1 Decisions on interchangeability and/or substitution rely on Member States 2 Member States have access to the scientific evaluation performed by the CHMP and all submitted data in order to substantiate their decisions 2 As interchangeability studies are not part of the registration requirements, such information may not be included in the EPAR 3 1. EMA. Q&A on biosimilar medicines, 2012; 2. EMA Procedural advice for users of the Centralised Procedure for Similar Biological Medicinal Products applications, 2014; 3. European Commission. Consensus Information Paper What you need to know about Biosimilar Medicinal Products,

10 EU/EMA: Interchangeability/Substitution for Biosimilars (2) The European Commission also recognizes that the studies reported in the literature were generally too short to show the possible long-term side effects of switching 1 No country has explicitly authorized the substitution of biological products from different manufacturers* 2 A number of EU Member States have put legal, regulatory and political provisions in place that prevent this practice 2 *At the time of publication of the consensus information paper from Tajani s initiative (April 2013) 1. European Commission. Consensus Information Paper What you need to know about Biosimilar Medicinal Products, 2013; 2. EuropaBio. Q&A Tajani s Initiative: Consensus information document on Biosimilars Medicinal Products,

11 Interchangeability and Substitution Worldwide Canada 1 Health Canada does not support automatic substitution, but allows physicians to determine interchangeability United States 2 FDA requirements to meet interchangeability threshold still unclear, automatic substitution of interchangeable drugs to be determined at state level Brazil, 6 Argentina, 7 Mexico 8,9 Developed guidelines for biosimilars, but have not yet addressed interchangeability or automatic substitution Chile 10 Interchangeability is possible provided it is a phased process and under the direction of a physician EMA 3,4 Decisions on interchangeability and/or substitution rely on national competent authorities and are outside the remit of EMA/CHMP Japan 5 Interchangeability and automatic substitution highly discouraged Australia 11,12 Under 2015 reforms, Australia s reimbursement body (PBAC) was granted primary responsibility for determining interchangeability. Whilst the PBAC has agreed to assess interchangeability on a case by case basis, a precedent has been set with the first mab biosimilar entrant receiving an a flag, allowing Pharmacy level substitution 1. Health Canada. Q&A on Information and Submission Requirements for Subsequent Entry Biologics, 2010; 2. FDA. Biosimilar Guidance Webinar Biosimilar Biological Products 2012; 3. EMA. Q&A on biosimilar medicines, 2012; 4. European Commission. Consensus Information Paper What you need to know about Biosimilar Medicinal Products, 2013; 5. MHLW. Guideline for the Quality, Safety, and Efficacy Assurance of Follow-on Biologics, 2009 by PhRMA; 6. ANVISA: Resolucao RDC N 55, de 16 de Deem bro de 2010; Diario Oficial da Uniao-Secao 1; N 241; 7. ANMAT, Disposición N 7729/2011 (publicado el 21 de Noviembre de 2011); 8. Proyecto de PROY-NOM-257-SSA1-2013; 9. Norma Oficial Mexicana. NOM-177-SSAI-2013; 10. Norma Técnica Nº 170 Sobre Registro Sanitario de Productos Biotecnológicos Derivados de Técnicas ADN Recombinantes; Diario Oificial de la República de Chile, 6 de Septiembre de 2014); 11. Australian PBAC recommendations. July Australian national health amendment bill

12 Demonstrating Interchangeability Why?

13 Why Should Interchangeability Be Clinically Demonstrated? Primary Concern: Immunogenicity Protein Folding Is a Multi-step Process 1 Amino acid chain Pleated sheet Alpha helix Pleated sheet Alpha helix Even minor differences in post-translational modification, folding and conformation can impact immunogenicity 5,6 1. UMass. Workshops, Short Courses and Seminars Kuhlmann & Covic. Nephrol Dial Transplant 2006;21:4 8; 3. Dorner T et al. Ann Rheum Dis 2013;72:322 8; 4. Goldsmith. Nephrol Dial Transplant 2006;21(Suppl 5):v1 3; 5. Scott et al. J Clin Pharmacol 2015;55:S123 32; 6. Chamberlain. Biosimilars 2014;4:

14 Immunogenicity 1,2 Incidence of immunogenicity: Varies widely between therapeutic proteins and studies Dependent on many factors, some currently unknown Difficult to predict Patient-related Patient characteristics Genetic variations in innate immunity Immune system integrity Disease state Factors affecting immunogenicity Treatment-related Dose and duration of treatment Route of administration Formulation and storage Additional unknown factors Biotherapeutic: Sequence and structure* Glycosylation and other posttranslational modifications Host cell line Contaminants/impurities *The more the sequence variation differs in structure from the native protein, the more immunogenic it is likely to be 1. Schellekens. Clin Ther 2002;24: ; 2. Schellekens. Nat Rev Drug Discov 2002;1:

15 Immunogenicity: Switching Challenges Formation of anti-drug antibodies can result in: No consequence, loss of efficacy, or hypersensitivity reactions 1 3 Monoclonal anti TNF antibodies may pose greater concern for immunogenicity than complex than proteins such as G-CSF 4 mabs are much larger at 148,000 daltons vs 18,464 daltons 5 Gaining a comprehensive understanding of the development, evolution and clinical impact of anti-tnf immunogenicity has taken several years and may not be easy to extrapolate to biosimilars 5 1. Schellekens. Nat Rev Drug Discov 2002;1:457 62; 2. Schellekens. Clin Ther 2002;24: ; 3. Shankar et al. AAPS J 2014;16:658 73; 4. Devlin et al. Can J Gastroenterol 2013;27:567 71; 5. de Riddler et al. J Pediatr Gastr Nutr 2015;61:

16 Measuring High Order Structure of Biologics Antibody Array ELISA 2 The 3D conformation of a biologic protein is an important factor in its function 1,2 However it can often be difficult to define precisely using current physiochemical analytical technology 1,2 Antibody-array technology was developed to characterize HOS of mabs: 2 Measures epitope exposure and compares conformational status of biosimilar to reference product Ab arrays can detect subtle changes not detected by any other analytical technologies 2 More than 30 polyclonal antibodies cover an entire mab Thereby measuring its surface-epitope distribution systematically and sensitively 2 1. CBER/CDER. Guidance for Industry Scientific Considerations in Demonstrating Biosimilarity to a Reference Product 2012; 2. Wang et al. BioProcess International 2014;12:32 7; Image reproduced with permission 16

17 Case Study Structure Alterations Affect Epitope Exposure and Immunogenicity Potential 1 HOS Comparability of Humira and BiosimilarmAbs * in the Constant Region-2 Color Change (OD 450mm) Polyclonal Antibody Humira Batches Biosimilar Batches MAb unfolding can raise the risk of immunogenicity by presenting new epitopes that usually are buried inside a MAb molecule on its surface. That increases the risk of breaking the tolerance of a patient s immune system 1 HOS: Higher Order Structure 1. Wang et al. BioProcess International 2014;12:32 7; Figure reproduced with permission * non-approved adalimumab biosimilar 17

18 Induction of the Immune Response According to the Prime-Boost Effect Persistent presence of an antigen induces an initial immune response followed by tolerance 1 It is well established that conventional B cells and T cells are anergized when an antigen is constantly present 2 Conversely, intermittent presence of an antigen (or epitope) promotes a persistent immune response that is similar to that seen in vaccination and vaccine recall 1 1. Schaeverbeke et al. Rheumatology 2015 [Epub ahead of print]; 2. Pradeu et al. Nat Rev Immunol 2013;13(10):764 9; Image reproduced with permission 18

19 Summary: Immunogenicity Switching Challenges Repeated switches between biosimilars and originators may increase immunogenicity with potentially negative effects 1 Conformational changes and epitope exposure may lead to the presentation of epitopes originally hidden within the mab 2 Additional epitope exposure could break self-tolerance and induce immunogenicity 2 1. Scott et al. J Clin Pharmacol 2015;55:S123 32; 2. Wang et al. BioProcess International 2014;12:

20 Demonstrating Interchangeability How?

21 Interchangeability: Switching Studies Despite the definition of interchangeability as stated by the FDA, there is no agreement as to the optimal clinical study design that should be used to demonstrate this concept 1 Potential factors to consider : Immunogenicity as an endpoint Patient population: Sensitivity, treatment-naive vs treatment-stable Analytical vs pharmacokinetic/pharmacodynamic/clinical surrogates Study duration, number of switches Non-inferiority vs equivalence 1. Dörner and Kay. Nat Rev Rheumatol 2015 [Epub ahead of print] 21

22 Interchangeability: Switching Studies Medical research involving human subjects may only be conducted if the importance of the objective outweighs the risks and burdens to the research subjects 1 What does this mean for a switching study where no clinical benefit is expected for (stable) patients while the potential risk is increased? Can access to affordable medications be considered a sufficient benefit for patients included in switching studies? 1. World Medical Association Declaration of Helsinki. JAMA 2013;310:

23 Interchangeability/Substitution and Extrapolation of Indications Can clinical interchangeability data be extrapolated from one tested indication to another? Currently not addressed by authorities or the scientific community 23

24 Interchangeability and Substitution in Clinical Practice

25 Interchangeability and Substitution Between Biologics A biological product may not be evaluated against more than one reference product 1 Will interchangeability transitivity be applied in practice? If A=B and A=C, does B=C follow? Reference Product A Biosimilar B Comparability studies are performed between a biosimilar and its reference product, but studies between one biosimilar and another are not done; two separate biosimilars may have been compared to the same reference but not between themselves 2 A C B Thus, switching between biosimilars is not desirable and there needs to be some way of distinguishing between one biosimilar and another and between the reference product 2 Biosimilar C, D,. 1. FDA Biologics Price Competition and Innovation Act 2009; 2. 56th Consultation on INN for Pharmaceutical Substances, Geneva: WHO, 2013, INN working document

26 Interchangeability, Substitution, Pharmacovigilance and Patient Management Post-marketing surveillance of the new and complex emerging class of biosimilar antibodies is critical 1 Substitution may increase the risk of misattribution of adverse events, especially if the onset of the adverse reaction is delayed 2 Some adverse reactions, including immunogenic reactions may develop only after several months 3 Several situations can be challenging: If physicians are not informed, it may subvert the ability to attribute adverse events to the appropriate agent 1 The package has been discarded 1 Inaccurate and/or incomplete patient s reporting of adverse reactions 1 In order to avoid misattribution of adverse reactions, physician and patient awareness of the drug prescribed should be maximized 1 1. Vermeer et al. Expert Opin Drug Saf 2015;14:63 72; 2. Dörner et al. Ann Rheum Dis 2013;72:322 8; 3. Casadevall et al. New Engl J Med. 2002;346:

27 Interchangeability, Substitution and Independent Product Manufacturing Changes Drift is the unintended change over time in some characteristic(s) of bioengineered products 1 Reference product Biosimilar Highly similar structure & function at time of approval Convergence OR Divergence OR No Change? While products may be highly similar at the time of approval Independent changes made by manufacturers may cause divergence, convergence or no change in their profiles over time 1,2 1. Ramanan & Grampp. BioDrugs. DOI /s z; 2. Kay, J et al. Biologicals 2012;40:517e527 27

28 Interchangeability, Substitution and Devices For self-injectable medications, should new patients be trained after switching? In order to prevent injection errors, how similar should the delivery devices be? FDA Guidance: 1 Additional considerations apply for a proposed interchangeable product. For example, in reviewing an application for a proposed interchangeable product, FDA may consider whether the differences from the reference product significantly alter critical design attributes, product performance, or operating principles, or would require additional instruction to healthcare providers or patients, for patients to be safely alternated or switched between the reference product and one or more interchangeable products without the intervention of the prescribing healthcare provider. Additional performance data about the delivery device may also be necessary MPA Statement: 2 Currently, these medical products are injected, which means that they may also be packaged in/supplied with different injection aids and hence are also unsuitable for substitution from this perspective. In addition, the approval of these products is tied into requirements of risk management plans which in many cases include follow up of safety for actual use. This would be hard to achieve if they are substituted for other products in a rolling manner at a pharmacy level 1. FDA. Guidance for Industry. Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009, 2015; 2. SMPA. Investigation of the possibility to extend the substitution system and of substitution for new prescriptions,

29 Summary

30 Conclusion (1) Biosimilarity approval by a regulatory agency does not imply interchangeability because: Biosimilars are not generic biologics 1 Biosimilars are made using a different host cell line and a different manufacturing process and are not identical to their reference product 1 Interchangeability of biologics or biosimilars could have clinical consequences and repeated switches may increase immunogenicity 2 According to the European Commission definition of interchangeability, any switching practice between biosimilars and their reference product should be done on the initiative, or with the agreement of the prescriber 3 1. WHO Guidelines on Evaluation of Similar Biotherapeutic Products. Geneva, Oct, 2009; Link; accessed 2015; 2. Scott et al. J Clin Pharmacol 2015;55(Suppl 3):S123 32; 3. European Commission. Consensus Information Paper What you need to know about Biosimilar Medicinal Products,

31 Conclusion (2) A biosimilar can be considered as interchangeable if the safety and reduced efficacy risks of alternating or switching are not greater than with repeated use of the reference product without alternating or switching 1 However, requirements to meet the interchangeability threshold are still to be defined 2 Some efforts are currently ongoing to define the optimal design for switching studies of biosimilars and their reference products, but challenges remain 3 5 Studies evaluating a single-sided switch from the reference product to the biosimilar cannot be regarded as demonstrating interchangeability 1. FDA Biologics Price Competition and Innovation Act 2009; 2. Dörner and Kay. Nat Rev Rheumatol 2015 [Epub ahead of print]; 3. Lu Y, et al. Drug Des 2013;3: ; 4. Endrenyi et al. Statist Med 2013,32:434 41; 5. Chow et al. Statist Med 2013;32:

32 Thank You