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June 2015
Joel Alvarez (C) 1
Using the eCTD Modelto Streamline the
Marketing Application Process g pp
Modules IV and V – Safety and Efficacy
Joel Alvarez, M.Sc.TAKEDA
June 23rd, 2015
About the Presenter
Joel Alvarez , M.Sc., is the Head of Global Regulatory Operations and Compliance for Takeda Vaccines Inc. In this capacity, Joel oversees global regulatory operational strategy, submission activities and implementation of systems and processes to ensure compliance worldwide Prioractivities, and implementation of systems and processes to ensure compliance worldwide. Prior to this, Joel was Director of Global Regulatory Operations and Technology at Shire Human Genetic Therapies Inc., where he led all technical functions pertaining to document and submissions management from development through post‐marketing for over 40 countries in North America, Europe, Asia‐Pacific and Latin America. Prior to joining Shire, Joel had held leadership positions at other leading bio‐pharmaceutical companies, including Wyeth, Millennium Pharmaceuticals, and Genetics Institute.
With over 18 years in the biopharmaceutical industry, and extensive practical experience in global regulatory submissions, electronic documentation, and content management, Joel has played an active role in the industry‐wide transition from paper to electronic submissions. Joel is a y p precognized industry leader in the development and implementation of agency and industry standards, and has spoken at numerous forums on best practices in submissions management and regulatory technology.
Joel holds a Bachelor of Science in Information Systems from So. New Hampshire University, and a Master of Science in Regulatory Affairs for Drugs, Biologics, and Medical Devices from Northeastern University.
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Development of a CommonSubmission FormatOrigins
International Conference of Harmonisation(ICH)(ICH)
US EU JP
FDA EU MHLW
PhRMA EFPIA JPMA
AGENCY:
INDUSTRY:
• Observers:– WHO– HC– EFTA
• Non-voting Member:– IFPMA
http://www.ich.org/home.html
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What is the CTD?
• Common Technical Document
– “common”, not global
• ICH set of specifications for marketing registrations.
• Agreement for the assembly of Quality, Safety, and Efficacy information in a common formatand Efficacy information in a common format.
• Sets the stage for standard electronic submissions.
The CTD Triangle
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CTD• Module 1: Administrative Information and Prescribing Information
Region‐Specific (e.g. application forms, prescribing information)
• Module 2: Common Technical Document SummariesCTD Introduction
• 2.3 Quality Overall Summary
• 2.4 Nonclinical Overview
• 2.5 Clinical Overview
• 2.6 Nonclinical Summary
• 2.7 Clinical Summary2.7 Clinical Summary
• Module 3: Quality
• Module 4: Nonclinical Study Reports
• Module 5: Clinical Study Reports
CTD Features (inc. paper CTD)
• Required as part of adopting ICH standards• Standardized structure and organization within ICH gregions• Module 2: Summaries• Module 4: Nonclinical Reports• Module 5: Clinical Reports
• Common presentation that can be setup to meet local/regional requirements
• Allows for presentation of overview and summaries (Module 2)
• Ease of review and navigation• Lifecycle maintenance (All Modules)
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The eCTD
• Electronic Presentation of the CTD
Including: defined structure, folders, document format and formatting, granularity, metadata, etc.
• More than just CTD in electronic form, the eCTD specifications detail the instructions on “how to” compile a compliant electronic submissiona compliant electronic submission
•
eCTD
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Module 2
• Nomenclature h ld bshould be harmonized
• SCS/SCE (high‐level summaries))vs ISS/ISE(data analysis)
Module II – Nonclinical SummariesModule IV ‐ Safety
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Module 2(Nonclinical Sections)
2 4 N li i l O i2.4 Nonclinical Overview
2.6 Nonclinical Written and Tabulated Summaries
2.6.1 Introduction2.6.2 Pharmacology Written Summary2.6.3 Pharmacology Tabulated Summary2.6.4 Pharmacokinetics Written Summary2.6.4 Pharmacokinetics Written Summary2.6.5 Pharmacokinetics Tabulated Summary2.6.6 Toxicology Written Summary2.6.7 Toxicology Tabulated Summary
Module 4Safety4.1 Table of Contents
4.2 Study Reports4.2.1 Pharmacology4.2.2 Pharmacokinetics4.2.3 Toxicology
4.3 Literature References
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M4: Nonclinical Study Reports
• Staggered completion of Modules
– CTD Module 4 is usually completed first
• Granularity
– In most cases, a single document per report
• Electronic reports are fully bookmarked and hyperlinkedhyperlinked
• Retain full‐text search functionality by scanning only individual pages as needed
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Nonclinical Study Report
Module II – Clinical SummariesModule V ‐ Efficacy
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Module 2(Clinical Sections)
2 5 Cli i l O i2.5 Clinical Overview
2.7 Clinical Summary
2.7.1 Summary of Biopharmaceutic Studiesand Associated Analytical Methods
2.7.2 Summary of Clinical Pharmacology Studies2.7.3 Summary of Clinical Efficacy2.7.3 Summary of Clinical Efficacy2.7.4 Summary of Clinical Safety2.7.5 Literature References2.7.6 Synopses of Individual Studies
• Tracking individual components in the submission preparation process.
• Establish strategy for multi-region submissions
Module 5Efficacy
• Establish strategy for multi-region submissions.– References to region-specific components.
– Planning CSRs for paper and electronic submissions.
• Text-based PDFs preferred; full-text search for pivotal studies is required.
• Placement of CSR components not listed in the ICH E3 guidanceguidance.
• “Not Applicable” sections
• External bookmarks connecting all CSR components for seamless navigation.
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Module 5Efficacy5.1 Table of Contents
5.2 Tabular Listing of All Clinical Studies
5.3 Clinical Study Reports5.3.1 Reports of Biopharmaceutic Studies5.3.2 Reports of Studies Pertinent to Pharmacokinetics
Using Human Biomaterials5.3.3 Reports of Human Phamacokinetics (PK) Studies5 3 4 R f H Ph d i (PD) S di5.3.4 Reports of Human Pharmacodynamic (PD) Studies5.3.5 Reports of Efficacy and Safety Studies5.3.6 Reports of Post‐Marketing Experience5.3.7 Case Report Forms and Individual Patient Listings
5.4 Literature References
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M5: Clinical StudyReports
• Organization followsICH E3 CSR G idICH E3 CSR Guidance
• Synopsis and Appendicesprovided as separate files
– Granularity supportsstaggered completiongg pand lifecycle
• Legacy Study Reports
Clinical Study Report
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Clinical Study Report
• Consider adding external bookmarks for “sibling”
sections when appropriate
Governing Principles
• Create submissions with a reviewer’s needs in mind.• Easy to locate information and references• Ability to copy portions of the document• Well‐organized and labeled documents – identify the most
current version of any document
• Build quality into the process.
• Global mindset –comprehensive approach to meet regulatory requirements in all applicable regions.
• Streamlined procedures for faster response time.
• Leverage technology
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eCTD Navigation and Cross‐Referencing
Navigation• Bookmarks that indicate the outline of sections within documents.
• Hyperlinks connect to related content that is referenced within the text.
• Features:
– Navigation throughout the submission
l f– Facilitate of review
– Easier access to content
• Contextual and Full‐Text Search
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Hyperlinks
• Standards in establishing a hyperlinking strategystrategy
“Navigation efficiency is also improved by providing hypertext links throughout the body of the document to supporting annotations, related sections, references, appendices, tables, or figures that are not located on the same page”
– For references to Study Reports strike balanceFor references to Study Reports, strike balance between narrative and ease of navigation
– Nonclinical/Clinical Summaries: Link to all M2 references
Lifecycle Management
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…Serial 000
Serial 078
2.5 clinical overview
Company Inc.
Company Inc.
…Serial 078
…Serial 120
2.6.1 introductionCompany Inc.
Company Inc.
Company Inc.
Company Inc.
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Lifecycle Management
Chronological View:
Lifecycle Management
Current View:
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Global Change ControlFramework
USUS eeCA eeAU/NZ eeEUCA AU/NZ EUUSUS eeCA eeAU/NZ eeEUCA AU/NZ EU
MX RU
amendment
• Living Document
• Organizational toolmapping documentation filed/needed
BR
SA
amendment
in each market
Note: not a common dossier.
Global Change ControlFramework
USUS eeCA eeAU/NZ eeEUCA AU/NZ EUUSUS eeCA eeAU/NZ eeEUCA AU/NZ EU
MX RU
amendment
• Integrate local teams in relevant global teams and/or team decisions.
• Technology: Able to
BR
SA
amendment
• Technology: Able to support timely evaluation and communication of changes.
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eCTDEnhanced Review Process
• Standard Structureand Organizationg
• Ease of Navigation
– ‘2‐Click’ Principle
– Bookmarks
– Hyperlinks
• Reduced use of paper
– Associated maintenance and
storage costs
eCTDEnhanced Review Process
• Better communication• Faster responseFaster response• Ease of retrieval• Access to completeinformation
• Improved content and document management
• Search: consumer web experience
• Full lifecycle management
