Biosimilars Scientific and Regulatory Considerations

Transcription

1 Biosimilars Scientific and Regulatory Considerations Gustavo Grampp Regulatory Policy Director, Amgen Presented at Maryland Pharmacists Association meeting January 31, 2016

2 Program objectives 1. Review complexities of biologics and differences from chemical drugs 2. Introduce the US biosimilar regulatory framework 3. Learn about biosimilar development including design, analytical studies, and clinical studies 4. Discuss post-approval considerations including pharmacovigilance, interchangeability, and substitution 2

3 INTRODUCTION TO BIOLOGICS 3

4 What is a biologic? Biologics are large protein-based therapeutics Biologics can include antibodies, recombinant proteins, or fusion proteins Monoclonal antibody Neiderwieser D et al. Eur J Haematol 2011;86:

5 What is a biologic? Biologics are more complex in structure and function than chemical drugs Up to 1000 larger 1,2 Monoclonal antibody 1 ~150 kda Acetylsalicylic acid 2 ~0.18 kda 1. Lipman NS et al. ILAR J. 2005;46: Aspirin prescribing information. Available at: Accessed September

6 What is a biologic? Biologics are more complex in structure and function than chemical drugs Complex, with post-translational modifications 1 Simple, 2 well-defined 3 Monoclonal antibody Acetylsalicylic acid 1. Roger SD. Nephrology 2006;11: Prugnaud JL. Br J Clin Pharmacol 2007;65: Genazzani AA et al. Biodrugs 2007;21:

7 Biologics are made by living cells through well-controlled processes A typical biotechnology manufacturing process includes multiple stages Transfection of DNA into host cell 1 Patient treatment 2 Cell line selection and Refrigeration, 2 development 1 storage, 2 and transport 1 Manufacturer establishes a unique master cell bank 1 Formulation, 1 fill, 2 and finish 2 Cell culture and expansion 1 Characterization and stability 2 Isolation 2 and purification 1 1. Kresse GB. Eur J Pharm Biopharm. 2009;72: Sharma BG. EJHP Practice. 2007;13:

8 So what is a biosimilar? According to the US FDA, a biosimilar is a biological product that is highly similar to the reference product There are no clinically meaningful differences in terms of: Safety Purity Potency In other words: Differences between biosimilars and reference biologics are expected, but must not be clinically meaningful FDA, Food and Drug Administration. US Food and Drug Administration. Available at: Accessed September

9 Each biosimilar is unique because of differences in manufacturing Known DNA sequence Unique manufacturing Unique biosimilar 1. Roger SD. Nephrology (Carlton) 2006;11: Mellstedt H et al. Ann Oncol 2008;19:

10 Biosimilars are fundamentally different from generics Biosimilars Generics Biosimilars Generics SIZE Monoclonal antibody Acetylsalicylic acid 1 STRUCTURE Monoclonal antibody Acetylsalicylic acid 1 Large 2 MW = ~150,000 Da 3 Small 2 MW = 180 Da 1 Complex with many options for posttranslational modification 4 Simple 5 and well defined 2 MANUFACTURING CHARACTERIZATIONS Each manufactured in a unique living cell line 2 Similar but not identical copy can be made 2 Predictable chemical process Identical copy can be made 2 Difficult to characterize fully owing to a mixture of related molecules 6 Easy to fully characterize 6 STABILITY IMMUNOGENICITY Sensitive to storage and handling conditions 2 Relatively stable 2 Higher potential 2 Lower potential 2 MW, molecular weight. 1. Aspirin comprehensive prescribing information. Available at: Accessed January Genazzani AA et al. Biodrugs 2007;21: Lipman NS et al. ILAR J 2005;46: Roger SD. Nephrology 2006;11: Prugnaud JL. Br J Clin Pharmacol 2007;65: Gottlieb S. Am J Health Syst Pharm 2008;65(Suppl 6):S2-S8. 10

11 Summary Biologics are large, complex medicines developed in living systems Biosimilars are highly similar, but not identical to the innovator biologic Biosimilars differ from generics in complexity, manufacturing and sensitivity 11

12 REGULATORY FRAMEWORKS 12

13 The US biosimilars pathway was signed into law along with the Affordable Care Act Generics Biosimilars Establish same active ingredient, strength, dosage form, route of administration, and condition of use Demonstration of bioequivalence Extensive structural and functional characterization Consider need for animal data to assess toxicity Clinical studies to compare clinical immunogenicity and PK/PD Sufficient to demonstrate that the product is highly similar to the reference product and safe, pure, and potent for one or more approved conditions of use FDA has discretion to determine that certain studies not required Food and Drug Administration. Accessed 24 January

14 In contrast to the regulatory framework for generics Same (Identity) = Identical (Identity) Pharmaceutical Equivalence Bioequivalence Therapeutic Equivalence Same active ingredients, dosage form, administration route & strength PE = Pharmaceutical Equivalence BE = Bioequivalence TE = Therapeutic Equivalence Same rate & extent of absorbance & availability at site (80-125%) Interchangeability Rating Same Structure = Same Function Steven Kozlowski, M.D. Director Office of Biotechnology Products/OPS/CDER. Available at

15 FDA recommends a Totality of Evidence and a stepwise approach for biosimilar development Clinical studies 1 Clinical Pharm. (PK/PD) Nonclinical Analytical Characterization (Structure & Function Assessment) Safety, Efficacy, and Immunogenicity One study to inform immunogenicity and will likely need at least one clinical study in a sensitive population to confirm safety and efficacy 2 The FDA will consider the totality of evidence provided 3 Comparative assessment of the structure and function Nonclinical evaluation Human PK/PD Clinical immunogenicity Clinical safety and efficacy, as needed The purpose of the biosimilar development program is to demonstrate that the biosimilar is highly similar to the reference product and not to independently establish its safety and effectiveness 3 The type and extent of analyses and testing that are needed to demonstrate biosimilarity will be determined on a case-by-case basis 3 FDA, Food and Drug Administration; PD, pharmacodynamics; PK, pharmacokinetics. 1. Kozlowski S. Presented at: Biotechnology Technology Summit; June 13, 2014; Rockville, MD. Accessed February 5, FDA. Guidance for Industry: Scientific Considerations in Demonstrating Biosimilarity to a Reference Product Accessed April 30, FDA. Guidance for Industry: Scientific Considerations in Demonstrating Biosimilarity to a Reference Product Accessed February 7,

16 Demonstration of biosimilarity is the first step - interchangeability has additional requirements Approved as a biosimilar Approved as an interchangeable biologic Additional evidence is needed to demonstrate interchangeability 1 Can be expected to produce the same clinical result as the reference product in any given patient AND For a product that is administered more than once, there is no additional risk in terms of safety or diminished efficacy as a result of switching between the biosimilar and the reference product compared with using the reference product alone The United States is the only country with a specific definition for an interchangeable biologic 2 Studies needed to obtain the interchangeability designation are not yet determined by the FDA 2 FDA, Food and Drug Administration. 1. Patient Protection and Affordable Care Act Accessed April 30, Camacho L, et al. Cancer Med. 2014;3:

17 Summary The US pathway for approval of biosimilars was signed into law along with the Patient Protection and Affordable Care Act A totality of evidence will be considered when evaluating a biosimilar product for approval Determination of interchangeability requires additional evidence 17

18 DEVELOPMENT OF BIOSIMILARS 18

19 Biosimilar manufacturers start with no knowledge of the reference product? Purchase and analyze reference product Determine amino acid sequence Characterize product, including glycosylation Understand structure function Determine critical quality attributes Kozlowski S. Presented at: Biotechnology Technology Summit; June 13, 2014; Rockville, MD. Available at: Accessed February

20 Biosimilar development requires reverse engineering, starting with reference product characterization Attributes related to the amino acid sequence and all post-translational modifications, including glycans Integrity of the secondary, tertiary, and quaternary structure Quantitative levels of product variants and their identities Properties of the finished drug product, including strength and formulation Higher order structure General properties and excipients Primary structure Product-related substances and impurities Stability Processrelated impurities Biological function Receptor binding and immunochemical properties Biological and functional activities, including receptor binding and immunochemical properties Impurities from host cells and downstream process Degradation profiles denoting stability Kinetics and thermodynamics of binding, related to functional activity US Food and Drug Administration. Available at: Accessed September

21 Biosimilar manufacturers create a unique cell line and a unique manufacturing process Known 1 DNA sequence Unknown 2 Cell line Growth media Method of cell expansion Bioreactor conditions Protein recovery conditions Purification conditions Formulation methods Reagents Reference standards Analytics Compare structure and function To reverse engineer a reference product, each biosimilar developer must create a manufacturing process for that biologic de novo 2 1. Mellstedt H et al. Ann Oncol 2008;19: Roger SD. Nephrology (Carlton) 2006;11:

22 A stepwise development program follows after reverse engineering Biosimilar? Originator BLA Biosimilar Clinical studies Nonclinical Biosimilar? 3. Clinical 2. Non-Clinical Cross reference Cross reference Analytical Characterization (Structure & Function Assessment) Biosimilar? 1. Quality Cross reference Prior findings of safety and efficacy Integrated Biosimilarity Exercise Quality, Safety and Efficacy Food and Drug Administration. Accessed 24 January

23 Stepwise assessment begins with extensive structural and functional comparisons Analytical Characterization (Structure & Function Assessment) Foundational for biosimilar development program Involves structural and functional characterization of reference product Involves the determination of differences in relevant critical attributes between biosimilar and reference product using appropriate analytical methodology FDA. Guidance for Industry: Scientific Considerations in Demonstrating Biosimilarity to a Reference Product Accessed February 7,

24 Comparisons assess alignment of many attributes, with emphasis on critical attribute General properties 1 Primary structure 2 High-order structure 2 Biological 2 Product-related substances and impurities 2 Process-related impurities 2 Particles and aggregates 1 Product degradation 2 Sample exercise: Biosimilar attributes compared with reference product 1 Attributes matched Attributes not matched, but not critical Attributes not matched and critical Biosimilar vs US reference product Biosimilar vs EU reference product Adapted from Foraker S, provided October 28, 2014, as part of an oral presentation and is qualified by such, containing forward-looking statements, and actual results may vary materially; Amgen disclaims any duty to update. ABP, Amgen biosimilar product; EU, European Union; US, United States. 1. Adapted from Foraker S. Accessed March 5, FDA. Guidance for Industry: Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product Accessed February 6,

25 Toxicity assessments based on data from animal studies are useful Nonclinical Animal toxicity data are useful when uncertainties remain about safety of biosimilar after extensive structural and functional characterization Not warranted if biosimilar has been demonstrated to be highly similar to reference through analytical characterization FDA. Guidance for Industry: Scientific Considerations in Demonstrating Biosimilarity to a Reference Product Accessed February 7,

26 Clinical pharmacology studies are a critical part of demonstrating biosimilarity Mean (±SD) serum concentration, µg/ml Comparative human PK and PD studies are fundamental components in demonstrating there no clinically meaningful differences between reference and biosimilar 1 Clinical Pharm. (PK/PD) PK studies should demonstrate similar exposure over time and PD studies should demonstrate similar effect on clinically relevant PD measure(s) related to efficacy or safety concerns 1 Important PK parameters that are commonly studied include AUC and C max 2 Example of PK of biosimilar that is highly similar to that of the reference 3 Biosimilar Reference AUC, area under the concentration-time curve; C max, maximum concentration; PD, pharmacodynamics; PK, pharmacokinetics; SD, standard deviation. a Biosimilar N=113. Figure reproduced from Park W, et al. Ann Rheum Dis. 2013;72: With permission from BMJ Publishing Group Ltd. 1. FDA. Guidance for Industry: Scientific Considerations in Demonstrating Biosimilarity to a Reference Product Accessed February 7, FDA. Guidance for Industry: Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference Product Park W, et al. Ann Rheum Dis. 2013;72:

27 Immunogenicity studies are critical for establishing biosimilarity Clinical Studies Clinical Pharm. PK/PD Safety, Efficacy, and Immunogenicity One clinical study in a sensitive population to inform immunogenicity 1 The goal of immunogenicity studies is to establish that there are no clinically meaningful differences in incidence and severity of human immune response between the biosimilar and reference product 2 PD, pharmacodynamics; PK, pharmacokinetics. Immunogenicity can be tested during clinical safety and efficacy studies, including PK/PD studies 1 Studies should be conducted in sensitive population 2 Studies should include assessment of binding and neutralizing antibodies 2 1. FDA. Guidance for Industry: Scientific Considerations in Demonstrating Biosimilarity to a Reference Product Accessed February 7, FDA. Guidance for Industry: Scientific Considerations in Demonstrating Biosimilarity to a Reference Product Accessed February 7,

28 Comparative clinical safety and efficacy assessments may address residual uncertainties Clinical Studies (Safety, Efficacy) 1 Clinical Pharm. (PK/PD) Nonclinical Analytical Characterization (Structure & Function Assessment) Factors that affect the type and extent of clinical efficacy and safety studies needed 2 Nature and complexity of the reference Mechanism of action of reference and disease pathology Extent of clinical experience with the reference and its therapeutic class Extent to which differences in structure and function studies predict differences in clinical outcomes Extent to which PK and PD studies predict clinical outcomes (eg, are sensitive PD markers available) PD, pharmacodynamics; PK, pharmacokinetics. 1. Kozlowski S. Presented at: Biotechnology Technology Summit; June 13, 2014; Rockville, MD. Accessed February 5, FDA. Guidance for Industry: Scientific Considerations in Demonstrating Biosimilarity to a Reference Product Accessed February 7,

29 Clinical confirmation: safety and efficacy Clinical Studies (Safety, Efficacy) The goal is to demonstrate that the biosimilar has neither decreased nor increased activity compared with the reference product and has similar immunogenicity Study design Two-sided test to demonstrate equivalence; with an appropriate equivalence margin A one-sided noninferiority design more appropriate in certain circumstances Endpoints and study population Important considerations Clinically relevant and sensitive in detecting clinically meaningful differences Selected by considering comorbidities and effect on disease state (eg, immunosuppressed) Clinical trial should allow Sufficient exposure Detection of relevant safety signals Detection of clinically meaningful differences in effectiveness and safety FDA. Guidance for Industry: Scientific Considerations in Demonstrating Biosimilarity to a Reference Product Accessed February 7,

30 Indication extrapolation is important to biosimilar development A proposed biosimilar product may be licensed in one or more additional conditions of use for which the reference product is licensed, without additional clinical trials, if appropriate scientific justification is provided Extrapolation is not automatic Reference product studies Biosimilar studies RA + PsO + PsA + AS + CD + UC RA + PsO Extrapolated indications + + PsA + AS CD UC AS, ankylosing spondylitis; CD, Crohn s disease; PsA, psoriatic arthritis; PsO, psoriasis; RA, rheumatoid arthritis; UC, ulcerative colitis. US Food and Drug Administration. Available at: 30 Accessed September 2015.

31 FDA recommendations address considerations related to extrapolation Considerations 1 FDA recommendations 2 Potential for distinct MOA in each therapeutic indication Extrapolation is considered on case-by-case basis When MOA is not fully understood, separate clinical trials in each indication are likely necessary Biological data covering all functional aspects of agent, demonstrating high similarity to reference, is required Variable optimal doses for efficacy or safety profiles in different patient groups Data are produced using patient population and clinical endpoint most sensitive to detect clinically meaningful differences in efficacy and safety Influence of individual patient characteristics on treatment response Careful consideration must be given to comorbidities/concomitant medications and intersubject variability FDA, Food and Drug Administration; MOA, mechanism of action. 1. Dörner T, et al. Ann Rheum Dis. 2013;72: FDA. Guidance for Industry: Scientific Considerations in Demonstrating Biosimilarity to a Reference Product Accessed February 7,

32 Summary: Pillars of Biosimilar Development Biosimilar development starts with reverse engineering of the reference product quality attributes Physiochemical and functional characterization of both the reference and the biosimilar is foundational to stepwise development Comparative human PK and PD studies demonstrating absence of clinically meaningful differences between reference and biosimilar are critical to establishing biosimilarity Immunogenicity testing demonstrating no clinically meaningful differences in incidence and severity is required It is likely that at least one clinical study in a sensitive population is needed to confirm safety and efficacy and inform immunogenicity Appropriate scientific justification is required to allow extrapolation of indications of use for which the reference is licensed FDA, Food and Drug Administration; PD, pharmacodynamics; PK, pharmacokinetics. 32

33 POST-APPROVAL CONSIDERATIONS 33

34 Ongoing pharmacovigilance is important for biologics and biosimilars Robust post-marketing safety monitoring is important to ensure similar safety and effectiveness between the biosimilar and the reference drug Safety monitoring should take into account the safety or effectiveness concerns associated with reference product Safety monitoring should have the ability to differentiate between adverse events associated with the proposed biosimilar product vs those associated with the reference drug or other biosimilars FDA. Guidance for Industry: Scientific Considerations in Demonstrating Biosimilarity to a Reference Product Accessed February 7,

35 Why the practitioner needs to know what product a patient received [C]ompanies will make manufacturing-related changes to biologics periodically and even small changes could affect safety or efficacy. FDA 1 Sensitivity and complexity Manufacturing changes Variability Justifies Safety Monitoring Immune response Potential drift between products Requires Doctors Office Access to accurate and complete medication histories Medical Records CVS for Refill #1 Patient Record Walgreens Refill #2 1. Kozlowski S et al. N Engl J Med. 2011;365: Independent pharmacy Refill #3 35

36 Proximal agent is not always the casual agent! Class effect vs. product specific effect Source: Casadevall Nicole, Immune-response and adverse reactions: PRCA case example. Presentation to EMA Nov, Available at

37 Interchangeability will require additional evidence beyond approval as a biosimilar Approved biosimilar Additional evidence is needed to demonstrate interchangeability 1 Can be expected to produce the same clinical result as the reference product in any given patient AND For a product that is administered more than once, there is no additional risk to safety or efficacy as a result of switching between the biosimilar and the reference product Approved, interchangeable biosimilar The US is the only country with a specific definition of an interchangeable biologic 1. US Food and Drug Administration. Available at: Accessed September

38 In the US, state regulations govern automatic substitution FDA approves a biologic as interchangeable with the reference product 1 Automatic substitution of an interchangeable biologic is allowed State pharmacy practice laws allow for substitution of an interchangeable biologic 2 1. US Food and Drug Administration htm. Accessed February NCSL. State Laws and Legislation Related to Biologic Medications and Substitution of Biosimilars Accessed April 4,

39 Summary Ongoing safety monitoring is critical to ensuring patient safety. FDA has proposed a system of distinguishable nonproprietary names to help facilitate accurate and timely adverse event reporting. FDA determines interchangeability and states determine the terms of pharmacy substitution of biologics 39

40 THANKS! 40