Risk Based Review and the Management of Residual Uncertainty in the Regulation of Biological Products

Transcription

1 Risk Based Review and the Management of Residual Uncertainty in the Regulation of Biological Products Jeffrey C. Baker, Ph.D. Deputy Director, Office of Biotechnology Products, CDER IFPAC 2015 January 26, 2015, Arlington VA 1

2 The Disclaimer This presentation represents the views and perspectives of the speaker and should not be viewed or acted upon as FDA Policy or assumed to be an all inclusive list of FDA requirements. For official policy and guidance, contributors are directed to The speaker may be contacted at 2

3 Management of Residual Uncertainty

4 The reason I like the game chess is because each move has countless repercussions, but you're in charge of them. And it's your ability to see into the future and the effects of the decisions you've made that makes you either a good or not a good chess player. It's not luck. ---Bono

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6 Regulation of biological products in the US Biological products are a subset of drugs and are therefore regulated under the Food, Drug, & Cosmetic Act. Biological products are licensed for marketing in the United States under section 351 of the Public Health Service (PHS) Act using a Biologics License Application (BLA). The PHS Act also provides authority to immediately suspend licenses in situations where there exists a danger to public health.

7 Definition: Biological Product BPCI Act of 2009 revises the definition of biological product in the Public Health Service Act (PHS Act) to include protein :... a virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, protein (except any chemically synthesized polypeptide), or analogous product applicable to the prevention, treatment, or cure of a disease or condition of human beings Historically, some proteins have been approved as drugs under section 505 of the FD&C Act (e.g., human growth hormone), and other proteins have been licensed as biologics under section 351 of the PHS Act (e.g., blood factors). An application for a biological product must be submitted under section 351 of the PHS Act, subject to certain exceptions during the 10-year transition period that ends March 23,

8 FDA has developed the following interpretation of the statutory terms Protein and Chemically synthesized polypeptide. Protein: Any alpha amino acid polymer with a specific defined sequence that is greater than 40 amino acids in size Chemically synthesized polypeptide: Any alpha amino acid polymer that is made entirely by chemical synthesis; and is less than 100 amino acids in size. 8

9 Who reviews and approves BLAs? BLAs may be submitted to either the Center for Drug Evaluation and Research (CDER) or the Center for Biologics Evaluation and Research (CBER) CDER reviews applications monoclonal antibodies, therapeutic proteins extracted from plant, animals, or micro-organisms including recombinant versions of the proteins, and nonvaccine immuno-modulators. CBER reviews allergenics, blood product, vaccines, gene therapies, xenotransplantation products, and devices used to collect and safeguard blood and blood products.

10 A BLA is a scientific, data driven assertion that The drug is safe. The drug is pure. The drug is potent. The process and facilities used to manufacture safe, pure, and potent drug are very likely to do so reproducibly and predictably.

11 A BLA submission is an exercise in technical advocacy! I am the best player in the world and I am here to prove it. -- Bobby Fischer 11

12 Architecture of Assurance Assurance of Predictable, High Quality Product and Process Lab Data Pilot Data Site Mfg Data Quality Systems Development Program Tech Transfer Package Validation Master Plan The Process Flow Document Sound Science and Effective Engineering

13 Choices You sit at the board and suddenly your heart leaps. Your hand trembles to pick up the piece and move it. But what chess teaches you is that you must sit there calmly and think about whether it s really a good idea and whether there are other, better ideas. --Stanley Kubrick

14 Discovery Decision Phase Development Commercial Development Building Start-Up and Launch In the opening a master should play like a book, in the mid-game he should play like a magician, in the ending he should play like a machine. Continuous Learning and Improvement --Usually attributed to Rudolph Spielman but actually a misquote by Spielman of Irving Chernev

15 In order to improve your game, you must study the endgame before everything else. For whereas the endings can be studied and mastered by themselves, the middle game and opening must be studied in relation to the end game. -- Jose Raul Capablanca 15

16 While the goal (safe, effective, reproducible) remains the same there are several different styles of end game in the development of biopharmaceuticals. Accelerated Approval Fast Track Review Priority Review Abbreviated Pathway for Biologics Breakthrough Status 16

17 The decision to expedite a development program is exclusively a clinical decision, based upon seriousness of the disease, unmet medical need, and availability of therapy. Copies are available from: Office of Communications Division of Drug Information, WO51, Room 2201 Center for Drug Evaluation and Research Food and Drug Administration New Hampshire Ave., Silver Spring, MD Phone: ; Fax: druginfo@fda.hhs.gov gulatoryinformation/guidances/default.htm

18 Accelerated Approval The FDA Accelerated Review Program was initiated in 1992 to allow faster approval of drugs for serious conditions that fill an unmet medical need. Authorized under 21CFR.314(h), 21CFR 601(c), and Section 506(c) of the FD&C Act 18

19 Accelerated Approval A drug that treats a serious condition AND generally provides meaningful advantage over available therapies AND demonstrates an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit or Clinical endpoint that can be measured earlier than an effect on irreversible morbidity or mortality, reasonably likely to predict an effect Takes into account severity, rarity or prevalence of the condition and availability or lack of alternative treatments and sponsors must agree to conduct post-marketing confirmatory trials Must meet the same statutory standard for safety, effectiveness, and assurance of drug quality. 19

20 Priority Review Drug that treats a serious condition and if approved would provide significant improvement in safety and effectiveness FDA evaluates every original application for priority review designation. Sponsor can request priority review FDA grants priority review within 60 days of submission Shortens the review timeline specified by PDUFA from 10 to 6 months 20

21 Fast Track Review Drug that treats a serious condition Demonstrate potential to address unmet medical need Expedite development and review Frequent interaction with review team Potential Priority review Rolling submission to the BLA review 21

22 A Special Endgame for Biologics The Biologics Price Competition and Innovation Act of 2009 (BPCI Act) is a recent and significant revision of the PHS Act and was passed as part of the Affordable Care Act that President Obama signed into law on March 23, BPCI Act creates an abbreviated licensure pathway for biological products shown to be biosimilar to or interchangeable with an FDA-licensed reference product. 22

23 Chess problems demand from the composer the same virtues that characterize all worthwhile art: originality, invention, conciseness, harmony, complexity, and splendid insincerity." -- Vladimir Nabokov 23

24 What is an Abbreviated Licensure Pathway for Biological Products? A biological product that is demonstrated to be highly similar to an FDAlicensed biological product (the reference product) may rely for licensure on certain existing scientific knowledge about the safety, purity, and potency of the reference product. This new licensure pathway under section 351(k) of the PHS Act permits a biosimilar biological product to be licensed based on less than a full complement of product-specific preclinical and clinical data There is no abbreviated licensure pathway for related biological products not intended to be biosimilar. 24

25 Definition: Biosimilarity Biosimilar or biosimilarity is defined in Section 351 of the PHS Act to mean that the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components, and that there are no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity, and potency of the product *. *Section 7002(b)(2) of the Affordable Care Act, amending section 351(i) of the PHS Act. 25

26 Clinically Meaningful Differences Clinically meaningful differences could include differences in the expected range of safety, purity, and potency of the proposed and reference product. By contrast, slight differences in rates of occurrence of adverse events between the two products ordinarily would not be considered clinically meaningful differences. 26

27 Totality of the Evidence in the evaluation of biosimilars No one size fits all assessment : Clinical Animal Studies Clinical Immunogenicity FDA scientists will evaluate the applicant s integration of various types of information to provide an overall assessment that a biological product is biosimilar to an approved reference product. Clinical Knowledge e.g. Post-Market Experience Human Pharmacokinetics and Pharmacodynamics (PK/PD) Structural and Functional Characterization 27

28 Development Framework: Comparative Analytical Characterization Continuum Cannot be biosimilar Similar Needs additional information to determine if highly similar (e.g., additional analytical data, or other studies to determine if minor differences are clinically inactive components ) Highly similar Permits a selective and targeted approach to determine if biosimilar Highly similar with fingerprint-like similarity Permits a more selective and targeted approach to determine if biosimilar 28

29 Nothing excites jaded Grandmasters more than a theoretical novelty. Dominic Lawson, author of The Inner Game 29

30 Food and Drug Administration Safety and Innovation Act (FDASIA) signed into law July 9, 2012 Title I Prescription Drug User Fee Amendments of 2012 Title II Medical Device User Fee Amendments of 2012 Title III Generic Drug User Fee Amendments of 2012 Title IV Biosimilar User Fee Act of 2012 Title V Pediatric Drugs and Devices Title VI Medical Device Regulatory Improvements Title VII Drug Supply Chain Title VIII Generating Antibiotic Incentives Now Title IX Drug Approval and Patient Access Title X Drug Shortages Title XI Other Provisions For more information and the full text of FDASIA visit Regulatory Information : Legislation at 2/26/2015Next Steps in Developing the Nation s Risk Based Biosimilars Review Program and the Management Recovery of of Biological Residual Uncertainty Products XV, in the July Regulation 29, 2012, of J.C. Biological Baker, Products; CDER J FDA Baker, CDER/FDA, IFPAC

31 From FDASIA Title IX: Breakthrough Therapy Designation Criteria Serious Condition Preliminary clinical evidence-clinical comparison (e.g., head-to-head, add-on, historical controls) demonstrates substantial improvement over available therapy on one or more clinically significant endpoints The request for breakthrough designation is submitted during IND, ideally no later than endof-phase 2 and FDA will respond within 60 days of receipt of request Features FDA may grant Priority review ; Sponsor may request fast track designation All Hands on Deck mentally for FDA review team and sponsor Work to design most efficient and effective development program to confirm benefit and support approval (if warranted by the later data) Strong organizational commitment from CDER to success of program Early and sustained attention to expediting development of manufacturing process to support timely approval 31

32 Strong Organizational Commitment Increased involvement of senior managers Division Directors, Office Directors, Center leadership where appropriate Experienced review staff Cross Disciplinary Team Leader Scientific liaison within the review team Coordinates internal and external communication in collaboration with the Regulatory Project Manager Increased frequency of meetings and communications Advice to facilitate an efficient development program 32

33 Copies are available from: Office of Communications Division of Drug Information, WO51, Room 2201 Center for Drug Evaluation and Research Food and Drug Administration New Hampshire Ave., Silver Spring, MD Phone: ; Fax: plianceregulatoryinformation/guidances /default.htm

34 Excerpt from the draft guidance IX. GENERAL CONSIDERATIONS A. Manufacturing and Product Quality Considerations When sponsors receive an expedited drug development designation, they should be prepared to propose a commercial manufacturing program that will ensure availability of quality product at the time of approval. The proposal should consider estimated market demand and the commercial manufacturing development plan, especially with regard to manufacturing facilities, lifecycle process validation (including scale-up and comparability), methods validation, stability studies, and potency studies if applicable. The proposal should also include a timeline for development of the manufacturing capabilities with goals aligned with the clinical development program. The applicant should ensure that the manufacturing process is sufficiently developed in order to support the CMC section. Excerpt from Draft Guidance for Industry Expedited Programs for Serious Conditions Drugs and Biologics, June 2013, Contains non binding recommendations, Draft not for implementation; Italics are added for purposes of this presentation

35 propose a commercial manufacturing program that will ensure availability of quality product at the time of approval Status of product and process development programs Plans for specifying the control strategies should consider: CQAs for product and process intermediates Process controls including intermediate and release testing Container closure system Linkages tracking process, formulation, and presentation changes throughout development Assessment of stability data Risk based analysis of failure modes and residual uncertainty 35

36 The proposed commercial manufacturing program should include anticipated commercial operations Site sourcing and facilities issues for manufacturing, testing, and supply chain management Scale up, bridging, or comparability exercises Life cycle process validation plan Role of the Production Quality Management System Availability of product at time of launch Plans for assurance of market supply 36

37 Openings teach you openings. Endgames teach you chess! -- Stephan Gerzadowicz 37

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39 Chess teaches foresight, by having to plan ahead; vigilance, by having to keep watch over the whole chess board; caution, by having to restrain ourselves from making hasty moves; and finally, we learn from chess the greatest maxim in life - that even when everything seems to be going badly for us we should not lose heart, but always hoping for a change for the better, steadfastly continue searching for the solutions to our problems. -- Benjamin Franklin