Biosimilars in the U.S. - the long way to their first approval Wissenschaftliche Prüfungsarbeit zur Erlangung des Titels „Master of Drug Regulatory Affairs“ der Mathematisch-Naturwissenschaftlichen Fakultät der Rheinischen Friedrich-Wilhelms-Universität Bonn vorgelegt von Dr. Mayte Bewersdorff aus Hannover Bonn 2016 Betreuer und 1. Referent: Dr. Josef Hofer Zweite Referentin: Dr. Brigitte Brake Table of Contents - I - Table of Contents Table of Contents ...............................................................................................................................................................I List of Abbreviations ..................................................................................................................................................... III 1. Executive Summary ................................................................................................................................................ 1 2. Introduction ............................................................................................................................................................. 1 3. First biosimilar approval for filgrastim under 351(k) of the PHS Act in the U.S. ............................................. 2 3.1. Regulatory Framework in the U.S. .................................................................................................................. 2 3.2. Guidelines ........................................................................................................................................................ 5 3.3. Approval process for Zarxio .......................................................................................................................... 12 3.3.1. Timeline of the approval process for Zarxio ............................................................................................. 12 3.3.2. Summarized results comprising aBLA for Zarxio .................................................................................... 14 3.3.3. Discussion ................................................................................................................................................. 17 4. Comparison of approval of Zarxio in the U.S. and Zarzio in Europe .............................................................. 20 4.1. European Background Information on the Approval of Zarzio ..................................................................... 20 4.1.1. Regulatory Framework in Europe ............................................................................................................. 20 4.1.2. Guidance for similar biological medicinal products in Europe with regards to Filgrastim ....................... 21 4.1.3. Timeline for approval of Zarzio in Europe ............................................................................................... 26 4.2. Comparison of the sequence of the approval processes of Sandoz’ Filgrastim in Europe and the U.S. ....... 27 4.3. Comparison of studies submitted for approval of Sandoz’ Filgrastim in Europe and the U.S. ..................... 29 4.4. General Discussion ........................................................................................................................................ 45 5. Further biosimilar approvals in the near future? .............................................................................................. 47 6. Potential reasons for the delay of the first biosimilar approval in the U.S....................................................... 52 6.1. Legal basis ..................................................................................................................................................... 52 6.2. FDA ............................................................................................................................................................... 54 6.3. Potential Concerns ........................................................................................................................................ 55 6.3.1. Patent issues (“Patent dance”)................................................................................................................... 55 6.3.2. Extrapolation ............................................................................................................................................. 56 6.3.3. Substitution - interchangeability ............................................................................................................... 57 6.3.4. Immunogenicity ........................................................................................................................................ 58 6.3.5. Naming ..................................................................................................................................................... 59 6.4. Conclusion ..................................................................................................................................................... 60 7. Outlook - regulation of “ATMP-similars” .......................................................................................................... 62 8. References .............................................................................................................................................................. 65 Table of Contents - II - 9. List of Figures ........................................................................................................................................................ 74 10. List of Tables ......................................................................................................................................................... 75 List of Abbreviations - III - List of Abbreviations AAC Arthritis Advisory Committee aBLA abbreviated Biologic License Application ADA Anti-Drug Antibody ANC Absolute Neutrophil Count ATMPs Advanced Therapy Medicinal Products AUC Area under the Curve AUEC Area under the Effect Curve BLA Biologic License Application BPCI Biologics Price Competition and Innovation BPD Biosimilar Biologic Product Development BsUFA Biosimilar User Fee Act CAR Chimeric Antigen Receptor CBER Center for Biologics Evaluation and Research CDER Center for Drug Evaluation and Research CHMP Committee for Medicinal Products for Human Use CTD Common Technical Dossier EMA European Medicine Agency EU European Union FD&C Act Federal Food, Drug, and Cosmetic Act FDA Food and Drug Administration FDASIA Food and Drug Administration Safety and Innovation Act G-CSF Granulocyte-Colony Stimulating Factor HCT/Ps Human cells, tissues, or cellular or tissue-based products ICH International Council for Harmonisation IND Investigational New Drug MA Marketing Authorization MAA Marketing Authorization Application MIU Million International Units MoA Mode of action NDA New Drug Application OCTGT Office of Cellular, Tissue, and Gene Therapies ODAC Oncologic Drugs Advisory Committee PBPC Peripheral Blood Progenitor Cell PD Pharmacodynamic PDUFA Prescription Drug User Fee Act Ph.Eur. European Pharmacopoeia PHS Act Public Health Service Act PK Pharmacokinetic QTPP Quality Target Product Profile rG-CSF recombinant Granulocyte-Colony Stimulating Factor List of Abbreviations - IV - rhG-CSF Recombinant human Granulocyte-Colony Stimulating Factor ROI Return-on-investment U.S. United States w/o without 1. Executive Summary - 1 - 1. Executive Summary The first biosimilar approval in the United States (U.S.) has been awaited for a long time. Europe already started approving biosimilars in 2006. In contrast, in the U.S. the first biosimilar was only granted marketing authorization (MA) in 2015. This first abbreviated biologic license application (aBLA) was submitted to the FDA by Sandoz seeking licensure in the U.S. for their filgrastim going by the brand name Zarxio and can be regarded as a model case for the biosimilar approval process in the U.S. because neither guidance documents were published nor the regulatory aBLA pathway was established at the time Sandoz started their development program of Zarxio. The FDA had the opportunity to learn from this aBLA and to define and optimize their requirements for submission of an aBLA. This learning process is partly reflected in the finalized guidance documents published after the approval of the first biosimilar. Due to the ongoing learning process of the FDA while already assessing aBLAs, the publication of further guidance documents has been slowed down. There are key issues which the FDA still needs to decide on, e.g. extrapolation of data to indications of use which have not explicitly been tested in clinical trials and naming of biosimilars. Comparing the approval process of Sandoz’ filgrastim in the U.S. with the approval process in Europe reveals that the basic situation at the beginning of the development program was similar in terms of lacking finalized guidance documents and the lack of already approved biosimilars to learn from. Both procedures were of comparable duration. The main difference was the successive implementation of the procedures. Apparently the documentation submitted in the U.S. was more extensive than the European one, most likely due to improved test methods and additional “bridging studies” demonstrating high similarity of the European approved reference product, the U.S.- licensed reference product and the proposed biosimilar. It seems as if the FDA was more thorough in assessing the provided data than the EMA. Nonetheless, both agencies