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Developing Biosimilars in the US – The Dawn of a New Era?

Developing Biosimilars in the US – The Dawn of a New Era?






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    Developing Biosimilars in the US – The Dawn of a New Era? Developing Biosimilars in the US – The Dawn of a New Era? Presentation Transcript

    • Developing Biosimilars in the US – The Dawn of a New Era? Featured Speakers: Tom Fritz, Managing Partner . Swiftwater Group LLC Tom Stover, Ph.D., Associate Principal, Swiftwater Group LLC Copyright © 2010 Honeycomb Xtalks Inc.
    • Developing Biosimilars in the US – The Dawn of a New Era?SWIFTWATER GROUP Swiftwater Group was founded in 1998 by a small group of seasoned pharmaceutical consultants and industry veterans with the express purpose of taking a fresh approach to helping clients succeed. Our vision was – and remains today – to approach each client problem, challenge, or opportunity with customized, industry-specific solutions delivered by true life sciences experts. Integration We believe that the problems, challenges and opportunities that our clients wrestle with must almost always be tackled from multiple directions. Major decisions need to be based on a thorough understanding of the implications of non-clinical evaluation, clinical study design, manufacturing process and control, and how regulatory bodies will view the work. This is especially important when planning and coordinating projects to meet global objectives. At Swiftwater Group, we cross-train our consultants so they understand the integrated relationship of pharmaceutical development disciplines; our consultants with clinical expertise also know how to anticipate and identify process and regulatory issues that are likely to arise, while our CMC experts can identify cost-effectiveness issues and other challenges that can emerge during non-clinical studies. Ensuring our team has this full-spectrum development expertise across functional areas is a key to our – and your – success. Business Savvy Every client and client problem is unique. Some clients depend on outsourcing every aspect of development, from pre- clinical studies through Phase III trials. Other clients have expertise in Phase III Clinical Trials, but have had less experience doing "First in Man" studies. Others may have a deep pipeline and as a result are resource-constrained and need help managing the development of a growing a portfolio, or assistance with a specific therapeutic area or functional area. With extensive experience on the business side of pharmaceuticals, Swiftwater Group understands the tradeoff between time, money, and resources. Whether you are trying to meet investment milestones, beat competitors to the market, or create superior data, you can rely on Swiftwater Group to provide expert advice and service – on time and on budget. Copyright © 2010 Honeycomb Xtalks Inc.
    • Developing Biosimilars in the US – The Dawn of a New Era?Tom Fritz, Managing Partner Tom is a recognized expert in pharmaceutical development. He has spent more than 20 years working with companies both as an executive and as a consultant. He has developed and managed company-wide drug development programs and has been directly responsible for the successful completion of numerous clinical trials and regulatory submissions. He has deep expertise in pharmaceutical operations management, clinical and regulatory strategy, technical and operational due diligence, and operational set-up and restructuring. He also has an extensive background in both small and large molecule manufacturing and personally led the manufacturing function of a growing biopharmaceutical company. Tom has widespread drug development experience, having worked on successful product registrations in the United States, Europe, and Japan. Tom has an MS in veterinary physiology from South Dakota State University and a BS in animal science from Texas Tech University. He has also completed all of his studies for a PhD in metabolic biochemistry with a minor in pharmacology at the University of Arizona Cancer Center. Copyright © 2010 Honeycomb Xtalks Inc.
    • Developing Biosimilars in the US – The Dawn of a New Era?Tom Fritz, Managing Partner Tom focuses on all phases of pharmaceutical drug development. With his background in pharmacology, scientific writing, and business development, Tom serves an instrumental role in evaluating and planning integrated drug development programs and in preparing regulatory documents for global submission. Tom’s substantial experience in project management contributes to the organization, preparation, and critical quality review of documentation necessary for the regulatory review process. Tom has worked with both leading pharmaceutical companies and innovative biotechnology firms to develop and implement comprehensive CMC, nonclinical, clinical, and regulatory strategies for new chemical entities, 505(b)(2) pathway reformulations, and recombinant protein therapeutics, including a follow-on biologic. In addition to traditional CMC platforms, Tom also has experience working on multiple drug programs for therapeutics derived from plant sources. Tom earned both his PhD in Pharmacology and MBA, with a concentration in Intellectual Property Management, from the Pennsylvania State University. He completed a post-doctoral fellowship at the University of Pennsylvania, where he focused on novel drug delivery therapeutics. He also holds a BS in Biology from Washington and Lee University. Copyright © 2010 Honeycomb Xtalks Inc.
    • Developing Biosimilars in the US – The  Dawn of a New Era? Xtalks Discussion November 16, 2011
    • Agenda Background and Speaker Introductions Defining Biosimilars Biosimilar Development Challenges Complex Regulatory Landscape Integrated Drug Development – How Timing is Key Question and Answer Period6
    • Background & Speaker Introductions Tom Fritz Managing Partner, Swiftwater Group Areas of Expertise • Regulatory, clinical, and technical operations management Project Experience • 25 years experience managing drug development programs and leading cross functional teams • Previous Co-Founder, VP, and COO of ImaRx Pharmaceuticals Corp. • Deep experience with multiple plant-derived recombinant protein therapeutic programs, including regulatory strategy and CMC support • Extensive past interaction with US FDA on development of regulatory programs for follow-on-biologics (biosimilars)7
    • Background & Speaker Introductions Tom Stover, Ph.D. Associate Principal, Swiftwater Group Areas of Expertise • Regulatory affairs and strategies • Integrated drug development planning and CMC support • Project management Project Experience • Project lead on a plant-derived recombinant protein therapeutic as a follow-on biologic – managed the project through initial regulatory filings • Project lead on CMC support and CMC regulatory preparation for a recombinant protein therapeutic • Project lead on multiple manufacturing site technology transfers for global, commercial products (solid oral sustained-release, suppository, and oral suspension)8
    • Background & Speaker Introductions Why does Swiftwater Group know Biosimilars?  Extensive experience managing drug development for biologics 4Involved in developing an early biosimilar approval pathway with FDA Managed first biosimilar IND submission for plant-derived protein Significant experience with alternative expression systems Deep CMC knowledge in drug substance and drug product characterization and formulation development9
    • Agenda Background and Speaker Introductions Defining Biosimilars Biosimilar Development Challenges Complex Regulatory Landscape Integrated Drug Development – How Timing is Key Question and Answer Period10
    • FDA Definition of Biological Products Biologics can be composed of sugars, proteins, or nucleic acids or complex combinations of these substances, or may be living entities such as cells and tissues. Biologics are isolated from a variety of natural sources — human, animal, or microorganism — and may be produced by biotechnology methods and other cutting-edge technologies. Biological products include a wide range of products such as: CDER CBER 4 Recombinant Therapeutic Proteins 4 Blood and Blood Components 4 Monoclonal Antibodies 4 Somatic Cells and Tissues 4 Allergenics 4 Gene Therapy 4 Vaccines11
    • Defining Biosimilars The biologics market in the US is an incredibly attractive  market in which to develop biosimilars. Biologics sales have reached unprecedented levels (~$50B) 4 8 of 10 “Top Sellers” in US in 2016 will be biologics (83% of Top Ten Sales)* 4 Now common to have $5B/year sales of a single biologic Many biologics will lose patent protection in the next few years** * Source: Burrill & Co Biotech 201112 ** Source: Dean & Co, US Biosimilars Market
    • Defining Biosimilars A biosimilar is a well characterized and highly similar  version of an approved biopharmaceutical, not a “generic.” The 2010 Biologics Price Competition and Innovation Act (BPCIA) defines biosimilars with respect to US law. Biosimilar is defined as a biological product that: 4 is highly similar to an approved reference product notwithstanding minor differences in clinically inactive components 4 has no clinically meaningful differences to the reference product in terms of the safety, purity, and potency of the product. Interchangeable is defined as a biological product that: 4 may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product (subsection (k)(4))13
    • Defining Biosimilars Where does the world stand with biosimilars development?14
    • Defining Biosimilars Products on the market today* under 505(b)(2) in the US and as  biosimilars in the EU Name Active Name Active Omnitrope somatropin Abseamed epoetin alfa Fortical calcitonin‐salmon Binocrit epoetin alfa Hylenex hyaluronidase Biograstim filgrastim GlucaGen glucagon Epoetin alfa Hexal epoetin alfa Lovenox# enoxaparin sodium Filgrastim Hexal filgrastim # Lovenox was approved as ANDA Nivestim filgrastim Omnitrope somatropin Ratiograstim filgrastim Retacrit epoetin zeta Silapo epoetin zeta Tevagrastim filgrastim Valtropin somatropin Zarzio filgrastim15 *As of 28‐Oct‐2011
    • Agenda Background and Speaker Introductions Defining Biosimilars Biosimilar Development Challenges Complex Regulatory Landscape Integrated Drug Development – How Timing is Key Question and Answer Period16
    • Biosimilar Development Challenges Biologics pose many challenges to companies attempting to  make similar products.  Biologic Conventional Drug • Typically large molecule • Typically small molecule • Usually difficult to • Usually easy to characterize characterize the active physico-chemical properties ingredient other than by biological effects • Single biologic may have • Typically has one effect more than one biological effect • Partly defined by • Manufacturing easy to manufacturing process reverse engineer • Potential for different immune • Low likelihood of immune responses responses17
    • Biosimilar Development Challenges Because of the definition of Therapeutic Equivalence, it will  be difficult for biosimilars to achieve this status. Bioequivalence Pharmaceutical No significant difference in Therapeutic Equivalence the rate & extent to which Equivalence same active the active ingredient/moiety Substitutable or ingredient, becomes available at the interchangeable, dosage form, site of drug action when route of administered at the same administration, molar dose under similar and strength conditions “Totality of Evidence”18
    • Biosimilar Development Challenges Characterization Requirements for Biosimilars begin early on  in development: DNA and Protein. Characterization on the DNA Level (Genotype) 4 Genetic Sequence and Amino Acid Translation 4 Restriction digest map of construct 4 Copy number, integration number, and site location (plant) 4 Vector map and element description 4 Description of cloning process and clone selection 4 Genetic stability Characterization on the Protein Level (Phenotype) 4 Evidence of protein expression (i.e., western) 4 Confirmation of Primary Structure (i.e. peptide mapping) 4 Confirmation of Secondary Structure (i.e circular dichroism) 4 Confirmation of Tertiary/Quaternary Structure (i.e. ELISA or NMR) 4 Functionality by in vitro or in vivo assay19
    • Biosimilar Development Challenges Early Protein Comparability Data should be Discussed with FDA • Identity Examine biologic function and • Purity in vivo safety (including • Potency/Activity immunogenicity) Discuss Results with FDA • Identify product- and process-related Impurities • Set limits for Impurities • Demonstrate Lot-to-Lot Consistency20
    • Biosimilar Development Challenges Immunogenicity Guidance Assay Design, as adapted from  EMA Guidance  Are antibodies being Patient sample taken at appropriate time points produced? False Negatives Rejected Screening Assay False Positives Rejected Confirmatory Assay Bioassay Positive Samples Confirmed Characterization Content/titre, Class, Assess Correlation between Antibodies Specificity What are these Produced and Biologic Treatment antibodies and what effect is there on efficacy? Assays for Clinical Markers and Assessment or Response in Human Patients21
    • Agenda Background and Speaker Introductions Defining Biosimilars Biosimilar Development Challenges Complex Regulatory Landscape Integrated Drug Development – How Timing is Key Question and Answer Period22
    • Complex Regulatory Landscape Political Landscape of Biosimilars Approval Pathway Development May 2011 FDA Register Notice: 2012 November 2009 October 2010 proposed user fee program PDUFA for biosimilar and Senate votes: gives FDA Public Meeting: Reauthorization interchangeable biological biologics 12 years Implementation product (351(k)) exclusivity Challenges for BPCIA applications. ? Waxman bill introduced: President Obama regulatory pathway for signs the health 2012 Budget: Obama Guidance biosimilars that would care reform BPCIA proposes to cut Documents?? have provided a Act exclusivity from 12 to 2011 minimum of 5 years 7 years exclusivity to the March 2010 innovator February 2011 March 200923
    • Complex Regulatory Landscape Biologics and Biosimilars are subject to provisions of both the FD&C  Act and the PHS Act. Prior to the 2010 Biologics Price Competition and Innovation Act (BPCIA), “similar” biological products in the US were approved under 505(b)(2) PHS provides provisions for biologics and biosimilars FDCA requirements also apply to biologics and biosimilars under PHS24
    • Complex Regulatory Landscape A parallel pattern exists between conventional and biologic  regulations. “Follow-on Biologic” Conventional Drugs Biologic Drugs Substitutability/ Interchangeability Yes No Yes No Terminology “Generic” similar “Interchangeable” Biosimilar Biosimilar Application Type ANDA NDA BLA BLA (505(j)) (505(b)(2)) (351(k)) (351(k)) • Pharmaceutical • Same active moiety • Same clinical • Same MoA, Requirements Equivalence • Truncated result in any indication, • Bioequivalence nonclinical given patient route of admin, • Possibly clinical BE • If given more dosage, & safety/efficacy than once, must form/strength (usually single be • Demonstrate study) interchangeable comparability w/ RLD in 1+ studies25
    • Complex Regulatory Landscape FDA’s approval of Omnitrope® paved the way for biosimilar legislative guidelines. FDA denied citizen’s petition from innovator companies and approved a 505(b)(2) truncated data package for Sandoz’ Omnitrope in 2006 Approvable attributes of Omnitrope 4 Simple recombinant protein (single gene/single protein; nonglycosylated) 4 Understood MOA and qualified bioassays & biomarkers 4 Long history of clinical use of somatropin NDA data package included 4 Quality: direct comparison of DS & DP to reference product Approved despite different impurity profile and molecular variants 4 Nonclinical: rat weight gain assay, subacute tox (rat), & local tolerance (rabbit) 4 Clinical: 1 comparative PK/PD and 1 comparative pediatric Phase III Compared quality of US vs. EU Genotropin® to support the use of EU product26
    • Complex Regulatory Landscape Regulation and data expectations for biosimilars approval  are related yet remain distinct.Approved As Biosimilar FOB NationalSame reference product approved in territory X XProcess is product; full CMC data package X X XComparative studies (quality, nonclinical, clinical) X X XImmunogenicity assessed in humans pre- and post- approval X X XStability • Stress and accelerated stability studies X • Expire period: real time/real temperature X X • Compare accelerated stability against reference Optional XInterchangeability/substitutability Defined with clear expectations X X defined Substitutability state-levelExtrapolation of indications (justify in dossier) X X X Based on clinical experience, available literature data, mechanisms of action or the same receptor(s) X are involved in all indications Only reference product indications (no indications of other approved rh-protein products with similar X indicators Only if similarity between the SBP and the RBP has been convincingly demonstrated XInternational Nonproprietary Naming INN is independent from pathway to approval; requirement for pharmacovigilance X X Defined naming convention for non-proprietary and brand name X27
    • Complex Regulatory Landscape Imminent FDA guidelines will likely adopt a “Totality of  Evidence” approach to biosimilars. Anticipation of well-planned, streamlined, truncated process that offers a gateway to significant market opportunity 4 Lessons learned from EMA guidelines 4 Likely not as ominous as some have suggested Integrate various types of information on a case-by-case basis 4 Reflect on quality attributes throughout a biosimilar’s lifecycle 4 Risk-based approach to reduce residual uncertainty in nonclinical development 4 Clarify need for PD markers in cases where PK similarity is demonstrated 4 Address Phase III study design, surrogate endpoints, and immunogenicity testing 4 Extrapolation of indications and standards for interchangeability Paradigm shift in Sponsor and FDA interactions (user fee-driven)28
    • Agenda Background and Speaker Introductions Defining Biosimilars Biosimilar Development Challenges Complex Regulatory Landscape Integrated Drug Development – How Timing is Key Question and Answer Period29
    • Integrated Drug Development – How Timing is Key The success of a biosimilar approval will need to incorporate  an Integrated Drug Development approach. Create an integrated drug development plan 4 Build quality into the process and justify product - specific critical quality attributes (process is product) 4 Risk-based approach in safety and efficacy Advise 4 Early scientific advice from subject matter experts 4 Biosimilars product development meetings with FDA – Pre-IND 4 Consider PROGRAM advantages not just DRUG/BIOLOGIC advantages Consider IND and BLA/NDA timing 4 Advantages and disadvantages of accelerating a biosimilars program30
    • Integrated Drug Development – How Timing is Key Anticipated challenges or problems that you are likely to  encounter. Comparing biosimilar DS directly to reference product DS may be difficult Higher scrutiny on comparability exercise due to 4 Alternative expression system (e.g., plant, insect cells, or yeast) 4 Different manufacturing processing steps 4 Complex protein that is difficult to fully characterize (e.g., glycosylation) 4 Lack of sensitivity or reproducibility of in vitro methods Multiple or unknown MOA for biosimilar candidate Lack of available or clinically relevant biomarker(s) Unexpected immunogenicity concerns31
    • Considerations for Strategic Actions Be prepared to terminate or revise development plan if 4 Preclinical efficacy pharmacology results are not acceptable, i.e., unable to demonstrate bioequivalence 4 Drug substance yield, impurity profiles, bioburden are not acceptable 4 Unexpected and unfavorable findings in tox/path program 4 Evidence of lack of sameness in Phase 1 (PK & PD) or Phase 2 clinical trials Be prepared to accelerate development if 4 Preclinical efficacy pharmacology results are favorable 4 If there is a failure of existing suppliers to meet growing market demands32
    • Agenda Background and Speaker Introductions Defining Biosimilars Biosimilar Development Challenges Complex Regulatory Landscape Integrated Drug Development – How Timing is Key Question and Answer Period33
    • For more information about Biosimilars, please contact Tom Fritz, Managing Partner tfritz@swiftwater.com or 520-881-007634