Assembling the BLA for your Biologic, Biosimilar , and Biobetter

1. Assembling the BLA for your Biologic, Biosimilar, and Biobetter Suzanne M. Sensabaugh, MS, MBA IIR: Business of Biosimilars September 20, 2010

2. Workshop agenda • Contents of BLA submissions • Assessing the risk of immunogenicity • Pharmacovigilance plan • Subsection (k) BLAs

3. Purpose • Applicant asks FDA to approve a new drug so it can be marketed and sold in the US • Provides information, data, analyses so that FDA can make a decision that the drug is • Safe and effective for proposed use and the benefits must outweigh the risks • Labeling is appropriate • Manufacturing and controls are adequate to assure safety, quality, identity, purity, potency, and strength

4. Marketing Application stats • Largest and most complex applications filed with the Agency • Typically 400 to 1600 volumes in size • 400-500 pages/volume • User Fees apply • FY2010 $1,405,500 HartmannWillner LLC

5. BLAs and NDAs • A marketing application must be filed and approved to distribute a product in the US • For biologics either a New Drug Application (NDA) or a Biologics License Application (BLA) • BLAs are approved under the PHS Act and a license is granted • Most, but not all, biologics are approved under the PHS Act • Regulations are found in 21 CFR Part 600 • NDAs are approved under the FD&C Act • Regulations are found in 21 CFR Part 314 • Biologics approved under this mechanism include hormones and insulin

6. Common Technical Document • A Common Technical Document (CTD) is a global dossier developed through ICH that provides organization and format for marketing applications in all 3 regions [BLA and NDA in the US, Marketing Application Authorization (MAA) in the EU] • QSE • Quality = CMC, Safety = preclinical (in vitro and in vivo), Efficacy = human clinical

7. ICH Guidelines apply • M4: Organization of the CTD • M4E: The CTD — Efficacy • M4Q: The CTD — Quality • M4S: The CTD — Safety • FDA Guidance for Industry Submitting Marketing Applications According to the ICH-CTD Format — General Considerations • http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM080589.pdf

8. Guidance on guidelines • FDA Guidance interprets FDA regulations • FDA regulations interpret US law • FDA guidelines trump ICH guidelines • No guideline can cover all possibilities • Use common sense • Focus on the FDA reviewer • Change format if needed to facilitate understanding and evaluation • Plan ahead • Ask questions at your preBLA meeting • Begin populating the application as the data/results become available

9. Strategy versus contents • Drug development strategy should always be determined from the labeling backwards • MA written sequentially • For each technical section • Individual reports • Technical summary • Overall Summary of the entire application • Labeling (Package Insert) HartmannWillner LLC

10. The marketing application tells the biologic’s whole story, including what happened during the clinical trials, what the ingredients are, results of animal studies, how the drug behaves in the body, and how it is manufactured, processed, and packaged

11. 1 Regional Administrative Information 2.1, 2.2, CTD TOC and Introduction 2.4, 2.5 Nonclinical & Clinical Overviews 2.7 Clinical Summary 2.6 Nonclinical Written & Tabulated Summaries 2.3 Quality Overall Summary 5 Clinical Study Reports 4 Nonclinical Study Reports 3 Quality CTD pyramid

12. CTD modules • Module 1 (Administrative and prescribing information) • Index, labeling, establishment description, User Fee cover sheet, financial information • Module 2 (Summaries and overview) • Executive summary of application, summaries of CMC, preclinical and clinical • Module 3 (CMC details) • Structure, general properties, description of process, controls, validation, analytical methods, container/closure system • Module 4 (Nonclinical pharmacology and toxicology details) • In vitro pharmacology, single and repeat-dose toxicology studies, dose-range finding studies, reproductive and developmental toxicoloy, safety pharmacology • Module 5 (Clinical details) • Pharmacokinetics, pharmacodynamics, case report forms and individual patient listings, statistical analysis, literature references

13. Applications for biologics licenses (21 CFR 601) • Data derived from nonclinical laboratory and clinical studies which demonstrate that the manufactured product meets the requirements of safety, purity, and potency • Nonclinical laboratory studies must be conducted in conformance with Part 58 (GLPs) or a statement of noncompliance • Clinical studies must be conducted in compliance with Parts 56 (IRB) & 50 (IFC) • A full description of manufacturing methods • Data establishing stability of the product through the dating period

14. BLAs (cont’d) • Sample(s) representative of the product for introduction or delivery for introduction into interstate commerce • Summaries of results of tests performed on the lot(s) represented by the submitted sample(s) • Specimens of the labels, enclosures, and containers • A Medication Guide if required under Part 208 • Address of each location involved in the manufacture of the product • Financial certification or disclosure statement(s) or both for clinical investigators (Part 54) • A claim for categorical exclusion under 25.30 or 25.31 or an environmental assessment under 25.40 of this chapter

15. Exemptions • Applies to therapeutic DNA plasmid product, therapeutic synthetic peptide product of 40 or fewer amino acids, monoclonal antibody product for in vivo use, or therapeutic recombinant DNA-derived product • Exempt from including • Personnel & facility(ies) information • Records • General Safety testing

16. Administrative and prescribing information Module 1

17. APPLICATION TO MARKET A NEW DRUG, BIOLOGIC, OR AN ANTIBIOTIC DRUG FOR HUMAN USE (Form 356h) • Applicant information • Product description • Dosage form, strength(s), proper & trade names, indication(s) • Application description • Type of application, reason for submission • Establishment information • Locations, type of manufacture/testing, inspection readiness • Cross references • Contents • Signature • The applicant, applicant's attorney, agent, or other authorized official

18. I agree to update this application with new safety information about the product that may reasonably affect the statement of contraindications, warnings, precautions, or adverse reactions in the draft labeling. I agree to submit safety update reports as provided for by regulation or as requested by FDA. If this application is approved, I agree to comply with all applicable laws and regulations that apply to approved applications, including, but not limited to the following: 1. Good manufacturing practice regulations in 21 CFR Parts 210, 211 or applicable regulations, Parts 606, and/or 820. 2. Biological establishment standards in 21 CFR Part 600. 3. Labeling regulations in 21 CFR Parts 201, 606, 610, 660, and/or 809. 4. In the case of a prescription drug or biological product, prescription drug advertising regulations in 21 CFR Part 202. 5. Regulations on making changes in application in FD&C Act section 506A, 21 CFR 314.71, 314.72, 314.97, 314.99, and 601.12. 6. Regulations on Reports in 21 CFR 314.80, 314.81, 600.80, and 600.81. 7. Local, state and Federal environmental impact laws. If this application applies to a drug product that FDA has proposed for scheduling under the Controlled Substances Act, I agree not to market the product until the Drug Enforcement Administration makes a final scheduling decision. The data and information in this submission have been reviewed and, to the best of my knowledge are certified to be true and accurate. Warning: A willfully false statement is a criminal offense, U.S. Code, title 18, section 1001.

19. Administrative documents • Patent information on any patent that claims the drug, if applicable • Patent certifications (not for BLA) • Debarment certification • Field copy certification (not for BLA) • User fee cover sheet • Financial disclosure information • Letters of authorization for reference to other applications or drug master files • Waiver requests • Environmental assessment or request for categorical exclusion • Statements of claimed exclusivity and associated certifications

20. Labeling • Draft package & container labels, patient leaflets, information sheets, Medication Guides • Package Insert • Annotated to direct reviewers to the information in the application

21. Package Insert Indications and usage Dosage and administration Dosage forms and strengths Contraindications Warnings and precautions Adverse reactions Drug interactions Use in specific populations Drug abuse and dependence Overdosage Description Clinical pharmacology Nonclinical toxicology Clinical studies References How supplied Patient Counseling Section HartmannWillner LLC

22. Selected sections of Package Insert • Description • Trade and generic name • Dosage form and route of administration • Quantitative description of active ingredients • Sterility statement • Pharmacological or therapeutic class of drug • Chemical name and structure of formula • Pharmacology • Mechanism of action (animals and humans) • PK , PD, and ADME

23. Selected sections of PI (cont’d) • Clinical studies • Summary of human studies used to establish safety and efficacy • Indications and usage • Treatment, prevention, or diagnosis of disease • Adjunctive therapy • All indications are supported clinical studies • Contraindications • Situations when the drug should not be used • Age, gender, disease states, concomitant therapy, etc.)

24. Selected sections of PI (cont’d) • Adverse Reactions • Adverse events to drug or related class of drug • Listed by organ system, severity, and frequency • Drug abuse and dependence • Controlled substance • Abuse potential • Physiological or physical dependence • Overdosage • Signs and symptoms • Complications • Drugs to counteract overdose

25. Selected sections of PI (cont’d) • Dosage and administration • Usual dosage and dosage range • Dosage regimen • Duration of treatment • Modifications needed for special population • Storage conditions • How supplied • Dosage forms • Packaging • Distribution information

26. CTD overviews & summaries Module 2

27. Module 2 structure • 2.1 Table of contents • 2.2 Introduction • 2.3 Quality Overall Summary • 2.4 Nonclinical Overview • 2.5 Clinical Overview • 2.6 Nonclinical Summary • 2.7 Clinical Summary

28. Quality Overall Summary • Critical key parameters of the product • Overview of analyses and data provided in the Quality section • Justification when guidelines not followed • Discussion of key issues integrating information from other sections • Do not include new information/data • Should not exceed 80 pages of text (not to include tables and figures)

29. Challenges introduced by the molecule • Physicochemical testing alone is insufficient to characterize the product, especially higher order structure • Side effects can result from binding to receptors other than the target • Lack of effectiveness can result from binding to receptors other than the target • Biopharmaceuticals can have more than one activity • Monoclonal antibodies - antigen binding and effector functions • “Superagonist” effect leading to exaggerated activation and proliferation

30. Manufacturing challenges • Development program must address potential safety and efficacy issues arising from • The manufacturing process • Impurities derived from the manufacturing process, such as HCP, host cell DNA, protein inducers • Contaminants, such as adventitious agents • Components used to support the growth of living cells may be of animal or human origin • The molecule • Molecular variants (product-related impurities), such as aggregation, oxidation and deamidation • Product degradants should be characterized using accelerated and stress stability studies

31. Manufacturing challenges (cont’d) • Process controls and in-process specifications are dependent on the manufacturing process and, thus, are unique to each process • Frequent manufacturing changes during development require a demonstration of comparability through comparability programs and protocols

32. MODULE 2 QUALITY OVERALL SUMMARY 2.3 INTRODUCTION TO THE QUALITY OVERALL SUMMARY 2.3.S DRUG SUBSTANCE 2.3.S.1 General Information 2.3.S.2 Manufacture 2.3.S.3 Characterization 2.3.S.4 Control of Drug Substance 2.3.S.5 Reference Standards or Materials 2.3.S.6 Container Closure System 2.3.S.7 Stability 2.3.P DRUG PRODUCT 2.3.P.1 Description and Composition of the Drug Product 2.3.P.2 Pharmaceutical Development 2.3.P.3 Manufacture 2.3.P.4 Control of Excipients 2.3.P.5 Control of Drug Product 2.3.P.6 Reference Standards or Materials 2.3.P.7 Container Closure System 2.3.P.8 Stability 2.3.A APPENDICES 2.3.A.1 Facilities and Equipment 2.3.A.2. Adventitious Agents Safety Evaluation 2.3.A.3 Novel Excipients 2.3.R REGIONAL INFORMATION BLA CMC (CTD format) ICH - Guidance for Industry - M4Q: The CTD - Quality

33. What to include • Introduction • Proprietary and non-proprietary name, dosage form, strength(s), route of administration(s), proposed indication(s) • Drug Substance • General information • Nomenclature, proper name/established name, amino acid sequence, molecular mass, physicochemical and other relevant properties, biological activity, etc.

34. What to include (cont’d) • Manufacture • Information and responsibility of each manufacturer, to include contractors and testing facilities • Brief description of the manufacturing process and controls • A flow diagram • Be sure it is sequential (vial to flask inoculum to cell culture to harvest to storage of drug substance) • Include • Any alternative processes and reprocessing • Any intermediate • List of materials • Specifications

35. Upstream process (fermentation) In-process controls Step In-process testing °C, pH, vvm, volume, rpm, hrs Seed culture pH, OD, non-host contamination °C, feed rate, psig, vvm, rpm, pH, DO Fermentation pH, OD, components, cell weight UV, LAL, SE-HPLC °C, hrs, flow rate, % solids Harvest Intermediate (biomass)

36. Intermediate (ICH Q5C) • A material produced which is not the drug substance or the drug product but whose manufacture is critical to the successful production of the drug substance or the drug product • Specifications are established • May undergo further molecular modification • May be held an extended period of time prior to further processing

37. Downstream process (purification) In-process control Step In-process testing pH adjustment, depth filtration pH Bed height, flow, loading density Column chromatography UV, LAL, RP-HPLC, pH, SDS-PAGE, appearance UV [initial], diafiltration volume, [final] Concentration, diafiltration Active Pharmaceutical Ingredient (Drug Substance)

38. Drug substance manufacture (cont’d) • Description of filling procedure and process controls • Description of the source and starting materials and materials of biological origin • Discussion of the selection and justification of critical manufacturing steps, process controls and acceptance criteria • A description of process validation • A brief summary of major manufacturing changes made throughout development and conclusions from the assessment used to evaluate product consistency • Be sure to reference nonclinical and clinical studies • Include batch numbers

39. What to include (cont’d) • Characterization • A description of the desired product and product-related substances • Summary of general properties, characteristic features and characterization data • Primary and higher order structure and biological activity • Control • Brief summary of the justification of the specifications, analytical procedures, and validation

40. What to include (cont’d) • Reference standards • Container closure system • Stability • Summary of studies • Conditions, batch numbers, analytical procedures • Brief discussion of results and conclusions • Proposed storage conditions and expiration dating period • Include a post-approval stability protocol

41. Drug product • Description and composition • Pharmaceutical development • Summary of the composition of the different formulations used in the clinical trials • Manufacture • Control of excipients • Control of drug product • Include characterization of impurities • Reference standards • Container closure system • Stability

42. Impurities (ICH Q6B) • Process-related: Impurities that are derived from the manufacturing process. They may be derived from cell substrates (e.g., host cell proteins, host cell DNA), cell culture (e.g., inducers, antibiotics, or media components), or downstream processing (e.g., processing reagents or column leachables). • Product-related: Molecular variants of the desired product (e.g., precursors, certain degradation products arising during manufacture and/or storage) which do not have properties comparable to those of the desired product with respect to activity, efficacy, and safety. • Truncated forms, deaminated forms, isomerized, oxidized or altered conjugated forms • Can lead to the development of immunogenicity due to the formation of neoepitopes and aggregates

43. Impurities(cont’d) • May be of known structure, partially characterized, or unidentified • Must be characterized to the extent possible • Biological activity should be evaluated, if possible • Methods for evaluation include immunoassays, hybridization techniques, HPLC, SDS-PAGE, MS, etc.

44. Appendices • Facilities and equipment • Adventitious agents safety evaluation • Excipients

45. Regional information • Executed Batch Records • Method Validation Package • Comparability Protocols

46. Nonclinical Overall Summary • Overall analysis of information in the nonclinical study reports section • Not to exceed 30 pages • Integrated critical assessment of the pharmacologic, pharmacokinetic and toxicologic evaluation of the drug • Justify any deviation from the guidelines • Discuss and justify nonclinical testing strategy • Integrate nonclinical findings with quality characteristics, results of clinical trials and/or effects with related products • For example, impurities • Nonclinical, clinical and marketing batches • Integrate across studies and species, and to human exposure given maximum intended doses

47. Structure • 2.4.1. Overview of testing strategy • 2.4.2. Pharmacology • 2.4.3. Pharmacokinetics • 2.4.4. Toxicology • 2.4.5. Integrated review and conclusions • 2.4.6. References

48. ICH Guidances • S1 Carcinogenicity • S2 Genetic toxicity • S3 Toxicokinetics • S4 Toxicology • S5 Reproductive toxicity • S6 Biotechnology • S7 Safety Pharmacology • S8 Immunotoxicity • + FDA Guidance documents

49. Clinical Overview • Discussion and interpretation of findings with nonclinical findings and quality data • Provides useful information to Agency reviewers of other CTD sections • Refer to data in the comprehensive summary, individual study reports and other relevant reports • Present conclusions and implications of data, strength and limitations of the development program and study results, risk:benefit analysis, and describe how study results support the prescribed labeling • Provide interpretation of how safety and efficacy findings support the proposed dose and indication(s)

50. Clinical Overview (cont’d) • Evaluation of how prescribing information and other approaches will optimize benefits and manage risk • Discuss safety and efficacy issues encountered during development, their evaluation and resolution • Explain why unresolved issues are not considered to be barriers for approval and describe plans to resolve them • Present justification for important or unusual aspects of the prescribing information