US FDA update: Recent Trends in the Regulation of Biopharmaceuticals

Transcription

1 US FDA update: Recent Trends in the Regulation of Biopharmaceuticals CMC Strategy Forum Europe 2017 Chana Fuchs Division of Biotechnology Review and Research IV Office of Biotechnology Products OPQ,CDER, FDA

2 Disclaimer The views and opinions expressed should not be used in place of regulations, published FDA guidances, or discussions with the Agency 2

3 Who Reviews your Biotechnology CMC submissions? Office of Program & Regulatory Operations (OPRO) Office of Policy for Pharmaceutical Quality (OPPQ) Office of Biotechnology Products (OBP) Office of New Drug Products (ONDP) Office of Lifecycle Drug Products (OLDP) Office of Process & Facilities (OPF) Office of Surveillance (OS) Office of Testing & Research (OTR) The Office of Pharmaceutical Quality assures that quality medicines are available for the American public. 3

4 Team-based Integrated Quality Assessment Strengthen the effectiveness of lifecycle quality evaluations by using team based processes, cross disciplinary interactions and joint problem solving. Enhance quality regulation by developing and utilizing staff expertise Integrates review and inspection activities across product lifecycle for a quality assessment Provides aligned patient-focused and risk-based drug product quality recommendations drug substance, drug product, manufacturing, and facilities Approximately 20 BLAs have been approved so far employing the IQA approach 4

5 Office of Biotechnology Products OBP DBRR I DBRR II DBRR III DBRR IV *DBRR: Division of Biotechnology Review and Research OBP is responsible for the quality review of monoclonal antibodies and most therapeutic proteins at CDER. # of approved applications (OBP) * * As of April

6 Development of Monoclonal Antibody Products raxibacumab Orthoclone 1 st mab ReoPro Rituxan Zenapax Enbrel Mylotarg Zevalin Humira Vectibix Cimzia Adcetris Gazyva Blincyto Inflectra Murine Intact chimeric humanized Chimeric fragment Fc-fusion Adapted from M. Shapiro, 2013 mab-drug Conjugate NDA Therapeutic radioimmunoconjugate Human/ phage display Human/ mouse Pegylated mab-drug Conjugate BLA Animal rule Bispecific Glycoengineered QbD/design space Biosimilar 77 antibody products 6 6

7 Advancement of Antibody Products mab s Advancements in knowledge and understanding: Product Structure/Function Structure & Modification Stability/Formulation Process Scale-up Platform/Platform-like knowledge Technology Manufacturing Analytical 7 7

8 CDER s Emerging Technology Team Goal: Encourage and support the adoption of innovative technology to modernize pharmaceutical development and manufacturing. Innovative or novel product, manufacturing process, or analytical technology subject to CMC review Existing or planned submission(s) Emerging technologies are generally unfamiliar, and therefore have limited or no regulatory precedence. ETT: A small cross functional team that provides expertise and input for innovative technologies. Contact ETT at CDER-ETT@fda.hhs.gov for proposals, presubmission meetings, regulatory applications with Emerging Technology Component soffices/officeofmedicalproductsandt

9 Changing Landscape of Lifecycle Management/Control Strategies FDA is discussing and approving advancements including: Modification of control strategies for legacy products Changing expectations for control strategies at the time of initial BLA/PAS approval (without changing expectation of assurance of quality) Use of Prior knowledge to support development, process and product quality control strategies. Use of Continued Process Verification, Predictive Modeling, Multi-Attribute Methodology, as part of control strategies for BLAs Requires data and relevant information and evaluation to fully support the proposed control strategies. 9 9

10 Established Conditions Draft Guidance for Industry: Established Conditions: Reportable CMC Changes for Approved Drug and Biologic Products (May 2015) The Guidance is intended to clarify what aspects of an application should be established conditions The description of the product, manufacturing process, facilities and equipment, and elements of the associated control strategy, as defined in an application, that assure the process performance and quality of an approved product. Changes to the established conditions must be reported to FDA Sufficient detail should be provided in the application regarding the proposed established conditions to assure process performance and quality of the approved product. Rationale: 21 CFR 601.2, 21 CFR (d)(1), 21 CFR (a)(1) Changes should be reported to FDA : 21 CFR , 21 CFR

11 Established Conditions What they are: DS/DP manufacturing and testing facilities; source and specifications for starting materials for biological products; process, including in-process tests and sequence of operations, equipment, and process parameters and their ranges; specifications (tests/analytical procedures /acceptance criteria) for the DS, other components, in-process materials, and DP, Maintenance strategy for chemometric and/or multivariate models (e.g., for models that may have high impact on product quality), Container closure system specifications, etc. What they are not: Batch records (however manufacturing / control strategy changes may require updates that should be submitted); Development data; Characterization data; Validation data; Batch analysis data; etc. Where they are commonly located in the CTD: The relevant information would still be considered an established condition even if it is located in a CTD section not specified below [in the list that follows]

12 Established Conditions: Supportive of product, process, controls, etc. Relationship of the Control Strategy to Established Conditions The Control Strategy Overall control strategy including facility, environmental controls, etc. (Not typically reported in submission) All changes whether reportable or not should be managed by the sponsor s quality system Elements necessary to assure process performance and product quality 12

13 Comparability Protocols Draft Guidance for Industry: Comparability Protocols for Human Drugs and Biologics: Chemistry, Manufacturing, and Controls Information (April 2016). Guidance was revised to: provide more flexibility regarding filing procedures for a notification of change in a condition established in an approved application. include current pharmaceutical quality concepts. add an appendix to address commonly asked questions CPs can be used to manage post-approval changes to established conditions by employing: Effective use of knowledge and understanding of the product and manufacturing process. A robust control strategy. Risk management activities over a product's life cycle. 13 An effective pharmaceutical quality system. 13

14 Comparability Protocols Comparability protocols are frequently used for manufacturing changes submitted in a BLA or a PAS. Protocols for new working cell banks and reference materials, reprocessing, addition of a manufacturing facility, change in process. Common issues seen include: Lack of data to support analytical comparability acceptance criteria Analytical comparability acceptance criteria that are the same as release criteria Lack of mechanism for evaluating comparability of stability Requests for downgrade of subsequent submission(s) for changes that cannot be downgraded due to requirements in addition to analytical comparability, e.g., inspections CP (with or without requests for downgrade) for changes that would include requirements in addition to analytical comparability, However the protocol does not address the additional requirements, e.g., validation 14 14

15 ICH Q12 Lifecycle Management This guideline is intended to work with ICH Q8 to Q11 Guidelines and will provide a framework to facilitate the management of post-approval Chemistry, Manufacturing and Controls (CMC) changes in a more predictable and efficient manner across the product lifecycle. Introduce the concept of a post-approval management plan that can be used to proactively identify post-approval changes and the mechanism to submit and assess these changes by regulatory authorities (Assessors and Inspectors) Establish criteria for post-approval change management protocols that can be adopted by the ICH regions (enabling a harmonised proactive approach for lifecycle management) Encourage enhanced product development and control strategy approaches (Quality by Design (QbD)) providing opportunities for scientific and risk based foundations for postapproval change management plans 15 Final Concept Paper; Q12: Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management; dated 28 July

16 Expedited Programs For drugs that address an unmet medical need in the treatment of a serious or lifethreatening condition Intended to help ensure that therapies for these conditions are approved and available to patients as soon as it can be concluded that the therapies benefits justify their risks Allow for earlier attention to drugs that have promise in treating such conditions Fast Track Designation: Section 506(b) of FD&C Act added by section 112 of the Food and Drug Administration Modernization Act of 1997 (FDAMA), amended by section 901 of the Food and Drug Administration Safety and Innovation Act of 2012 (FDASIA) Priority Review Designation: Prescription Drug User Fee Act of 1992 Accelerated Approval: Section 506(c) Food, Drug & Cosmetic Act (FD&C Act) of the FD&C Act of 1992, amended by section 901 of FDASIA Breakthrough Therapy Designation: Section 506(a) of the FD&C Act, as added by section 902 of FDASIA,

17 Fast Track Designation Nonclinical or clinical data demonstrate potential to meet unmet medical need Features: Actions to expedite development and review: frequent interactions Rolling review (and may be eligible for priority review) Total Requests Received Granted Denied Draft ActivityReports/ucm htm Guidance for Industry: Expedited Programs for Serious Conditions Drugs and Biologics

18 Priority Review Designation Would provide a significant improvement compared to marketed products, in the treatment, diagnosis, or prevention of a disease. Features: Shorter clock for review of marketing application compared with standard review 6 months (from filing)/8 months (from receipt) vs. 10/12 month, respectively Priority Approvals CY 2016: 3 BLA approvals, 1 of which also had Orphan designation* CY 2015: 7 BLA approvals, 5 of which also had Orphan designation CY 2014: 8 BLA approvals, 7 of which also had Orphan designation CY 2013: 2 BLA approvals, 1 of which also had Orphan designation * Orphan Designation - Pursuant to Section 526 of the Orphan Drug Act (Public Law as amended). AandBLAApprovalReports/ucm htm 18

19 Accelerated Approval Approval based on an effect on a surrogate endpoint or an intermediate clinical endpoint that is reasonably likely to predict a drug s clinical benefit Requires post-marketing confirmatory trials to verify the anticipated clinical effect Approval of a drug may be withdrawn if trials fail to verify clinical benefit or to demonstrate sufficient clinical benefit to justify the risks associated with the drug Approvals CY 2016: 7 approvals (2 BLAs) CY 2015: 8 approvals (2 BLAs) CY 2014: 8 approvals (3 BLAs) Biotechnology product approvals include: Keytruda (pembrolizumab), Blyncito (blinatumomab), Opdivo (nivolumab), Praxbind (idarucizumab), Darzalex (daratumumab), Tecentriq (atezolizumab), Lartruvo (olaratumab) Reports/NDAandBLAApprovalReports/UCM pdf 19

20 Breakthrough Therapy Designation Clinical evidence indicating substantial improvement for a clinically significant endpoint over available therapies Features: Guidance on efficient drug development Granting meetings throughout the development of the drug Providing timely advice and interactive communication with the sponsor Taking steps to ensure that the design of the clinical trials is as efficient as practicable, when scientifically appropriate, such as by minimizing the number of patients exposed to a potentially less efficacious treatment Organizational commitment Assigning a cross-disciplinary project lead for the FDA review team to facilitate an efficient review and to serve as a scientific liaison between the crossdiscipline members of the review team Involving senior managers and experienced review staff Rolling review Other actions to expedite review (e.g., priority review designation) 20

21 Update on Breakthrough products Breakthrough therapy designation was enacted on July 9, 2012 in the Food and Drug Administration Safety and Innovation Act. CDER BT requests received: FY 2012: 2 requests, 1 granted, 1 denied 0 withdrawn FY 2013: 92 requests, 31 granted, 52 denied 9 withdrawn FY 2014: 96 requests, 31 granted, 51 denied 14 withdrawn FY 2015: 93 requests, 32 granted, 43 denied 18 withdrawn FY 2016: 106 requests, 46 granted, 48 denied 12 withdrawn FY 2017*: 52 requests, 9 granted, 15 denied 5 withdrawn Marketing Approvals CY : 24 new drug approvals (9 BLAs); 10 supplement approvals (7 BLAs) CY new drug approvals (3 BLAs); 12 supplement approvals (7 BLAs) CY 2017* 5 new drug approvals (3 BLAs); 3 supplement approvals (2 BLAs) *2017 data through March 31, ActivityReports/ucm htm 21 21

22 Breakthrough Therapy Products BT designation is intended to expedite the development and review of drugs for serious or life-threatening conditions Advanced knowledge Expedited CMC development, risk benefit evaluations Expedited product development, potentially more changes post-marketing BT designation does not change general CMC requirements and expectations. 10 of 45 novel drugs approved in 2015 were breakthrough 5 were biotech products: asfotase alfa, daratumumab, elotuzumab, idarucizumab, and sebelipase alfa (joining blinatumomab, nivolumab, obinutuzumab, pembrolizumab) 22 22

23 Expedited Development- Challenges The sponsor of a product that receives an expedited drug development designation will probably need to pursue a more rapid manufacturing development program to accommodate the accelerated pace of the clinical program. The sponsor s product quality team and CMC teams should initiate early communication with FDA to ensure that the manufacturing development programs and timing of submissions meet the Agency s expectations for licensure or marketing approval. e.g., discussions prior to process validation, changes to the manufacturing process, comparability studies, etc. Draft Guidance for Industry: Expedited Programs for Serious Conditions Drugs and Biologics

24 Expedited Development: Experiences and Challenges Expedited development requires a strong commitment and careful planning Process development and product characterization need to keep pace with clinical development A commercial manufacturing process needs to be ready to consistently deliver the clinical performance stated on the label and to meet market demand Sponsors should request CMC-specific meetings as soon as possible and should plan subsequent meetings carefully FDA challenges include resources, expedited review timelines, and some applications for licensure in which product/process knowledge is not as well developed as would be typical for standard development 24 24

25 Update on Biosimilars The Biologics Price Competition and Innovation Act of 2009 (BPCI Act) creates an abbreviated licensure pathway for biological products shown to be biosimilar to or interchangeable with an FDA-licensed reference product. Biosimilar or Biosimilarity means: that the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components; and 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. Requires advanced knowledge, analytical techniques to examine the reference product quality attributes, reverse engineering, process development, CQA understanding and risk ranking. 25

26 Update on Biosimilars As of May 1, 2017, there were 65 programs in the Biosimilar Product Development (BPD) Program for 23 different reference products Nine companies have publicly announced submission of fourteen 351(k) BLAs to FDA Five 351(k) BLAs for biosimilar products have been approved Zarxio (filgrastim-sndz) Inflectra (infliximab-dyyb) Erelzi (etanercept-szzs) Amjetiva (adalimumab-atto) Renflexis (infliximab-abda) 2 new Draft guidances : Draft guidance Considerations in Demonstrating Interchangeability With a Reference product. Jan 2017 Draft Guidance Nonproprietary Naming of Biological Products Jan

27 New Management: HHS Secretary: Dr. Tomas Price FDA Commissioner: Dr. Scott Gottlieb 27 27

28 Thank you for your attention Acknowledgements: Sarah Kennett Leslie Rivera-Rosado 28