KFDA Regulatory Framework on Biopharmaceuticals - Focus on Biosimilar Kyung-Min Baek, Ph.D. Recombinant Protein Products Division Korea Food and Drug Administration(KFDA)
Biopharmaceuticals A biopharmaceutical is a preparation derived from living organisms or their products and it require a special care for the sake of public health. This includes vaccine, plasma derivatives, antitoxin, recombinant DNA product, cell culture derived products, cell therapy products, gene therapy products and other products and agents with similar properties. (Regulation on Review and Authorization of Biological Products, KFDA notification) 2
Legislative Basis for Regulation Law Regulation Not legally binding Act Enforcement regulation of Act Notification Guidance Biopharmaceutical Related, The Pharmaceutical Affairs Act (PAA), The Communicable Disease Prevention Act, The Human Tissue Safety Control Act, The Blood Control Act Enforcement Regulation of the PAA - Good Manufacturing Practice for Biologics - Enforcement Decree on the Standards of Facilities of Pharmacies and Manufacturers, Importers and Distributors of Drugs, etc. Notifications - Regulation on Review and Authorization of Biological Products - Regulation on Drug Safety Information Management (Pharmacovigilance system) - Korean Minimum Requirements for biologics 3
Overview KFDA Organization of Regulatory Systems Re-evaluation Re-examination PSUR-like reporting PV plan reporting GCP, GLP GMP for IND CMC Safety and Efficacy GMP, GIP establishment licensing National lot release Planned or Special testing Periodic or Special inspection Advertisement 4
Organization of KFDA Commissioner Director General for Planning & Coordiantion 6 Regional Offices Risk Prevention Policy Bureau Food Safety Bureau Director General for Nutrition Policy Food Standardiztion Department Pharmaceutical Safety Bureau Drug Evaluation Department Biopharmaceuticals and Herbal Medicine Bureau Biopharmaceuticals and Herbal Medicine Evaluation Department Medical Device Safety Bureau Medical Device Evaluation Department 5
Responsible Offices Biopharmaceuticals & Herbal Medicine Bureau Biopharmaceutical Policy Div. Biopharmaceutical Quality Management Div. Herbal Medicine Policy Div. Cosmetics Policy Div. Policy, Law & Regulations, GMP, Post-marketing controls Nat l Institute of Food and Drug Safety Evaluation Center for Drug Development Assistance Nat l Center for Lot Release Biologics Research Div. Biopharmaceuticals & Herbal Medicine Evaluation Department Biologics Div. Recombinant Protein Products Div. Cell & Gene Therapy Products Div. Herbal Medicinal Products Div. Cosmetic Evaluation Div. Review & Approval for Licensure 6 Regional Offices Product recalls, administrative actions Advanced Therapy Products Research Div. Testing, R&D, Consultation for drug Dev. 6
From Development to Authorization Preclinical Development Consultation for drug development Pre-IND meeting Phase I, II, III Clinical Trials 30-days KFDA review for IND approval Dossier Review for Quality, Safety & Efficacy Pre-NDA meeting NDA Approval 115 days KFDA review for NDA approval Dossier Review for Quality, Safety & Efficacy Pre-approval GMP inspection Product QC testing Sponsors have submitted application as electronic documents through online system since Oct. 2 nd, 2006. 7
Dossier for NDA Components of Dossier for NDA - Submission of CTD form is possible 8
Post-marketing Controls 1. Regular or Special Facility Inspection 2. Pharmacovigilance 3. National Lot Release Testing 4. Regular or Periodic Product Testing 5. Advertisements, Counterfeit Drugs 9
Pharmacovigilance Product Approval PMS (Mandatory) ADR Monitoring (Voluntary, Mandatory) Sponsor PMS Report Safety Information(AE) Report - Immediate Report - Annual Report If necessary, CPAC Consultation Review PMS result Evaluation of Safety Information * CPAC : Central Pharmaceutical Advisory Committee KFDA License Amended 10 Follow-up actions - Product Withdrawal - Product License Amendment - Investigation - Management as Signal - Safety Alert/Letter
PMS 1. Objectives - Monitoring their safety information at the first level after approval : Investigate and determine ADR which did not arise during the drug development, and update drug approval 2. Items and PMS Period items - New drugs - Drugs whose active drug substance or compound ratio is different from approved drugs - Drugs whose active drug substance is same, but route of administration is different from approved drugs - Drugs whose active drug substance and route of administration is same, but indication is clearly different - Other drugs which need for re-review period 6 years 4 years 11
Biosimilar Regulatory Framework in Korea Regulation on Approval and Review of Biopharmaceutical Products (KFDA Notification No. 2009-56) was amended to establish a regulatory pathway for biosimilar product in September, 2009 Guideline on Evaluation of Biosimilar Products and Questions & Answers regarding Biosimilar Guideline were issued in September, 2009 12
Principles of the Biosimilar Approach The approval of the biosimilar product should be based on the demonstration of similarity to a chosen reference drug The comprehensive characterization and comparison at quality level should provide a basis for a reduction in the non-clinical and clinical data Regulatory decision making should be based on a comprehensive evaluation of quality, safety and efficacy data 13
Reference Product The reference drug should be already approved on the basis of a complete dossier package in South Korea Biosimilar products or abbreviated approved products should not be used as a reference drug The reference drug should be used throughout the studies supporting the quality, safety, and efficacy of the product Use of Non Korean reference product may be acceptable, if a sufficient information to justify the comparability to Korean reference product would be provided 14
Requirements for Quality Studies Full CMC and comparability exercise data between biosimilar product and reference product are required Extensive side by side characterization Physicochemical properties Biological activity Specification Impurities Stability The demonstration of similarity does not necessarily mean that the quality attributes of the two products will be identical The impact of observed differences in the quality attributes should be assessed 15
Requirements for Non-Clinical Studies Comparative non-clinical studies should be designed to detect significant differences between the biosimilar product and the reference product - In vitro study Receptor binding study, Cell based bioassay - In vivo study Biological/Pharmacodynamic studies relevant to the clinical application - Toxicity At least one repeat dose toxicity study in a relevant species, including toxicokinetic study, anti-drug antibody measurement 16
Requirements for Clinical Studies Comparative clinical trials are required depending on the data in terms of quality and nonclinical studies. Pharmacokinetic Studies/Pharmacodynamic Studies Clinical Efficacy & Safety trials Confirmatory PK/PD studies Equivalence trial is recommended, and equivalence margins should be pre-specified and justified Pre-approval safety data from sufficient number of patients and study duration should be provided to compare the nature, severity, and frequency of adverse reactions (including immunogenicity study) 17
Pharmacovigilance Generally, clinical safety data from pre-authorization studies are insufficient to identify the all potential safety profiles 4 year Post-marketing surveillance (PMS) of the safety profile is required The PMS study plan should be submitted and discussed with KFDA before marketing of a biosimilar product The findings obtained from the PMS study should be reported to KFDA periodically 18
Issue and Challenges in Biosimilar Review Use of Non-Korean reference products Determination of biosimilarity Extrapolation of indication Post-Marketing pharmacovigilance Inclusion of Korean patients in clinical trials : May be data for bridging study but still under discussion 19
Status of Biosimilar Applications in Korea KFDA-Industry Joint Meeting for Biosimilar Development Program 11 Biosimilar developing companies 24 Pre-IND sponsor meetings Scientific advice for 21 biosimilar products to 9 reference products 15 INDs approved (as of Oct, 2012) 1 Biosimilar product approved (July, 2012) Ramsima/Remicade biosimilar 20
Future Plans (Toward Regulatory Harmonization) Global harmonization on science-based decision making for high-quality biosimilar products Collaboration on capacity building for expertise Collaboration on information sharing Collaboration on post-market surveillance for patient safety 21
감사합니다. Thank You ありがとうございます Fax : 82-43-719-3500 E-mail : bkmwhite@korea.kr 22