Module 12 2019

©TOPRA ( The Organisation for Professionals in Regulatory Affairs) 2019

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Module 12: Data Management and Digitalisation in Regulatory Affairs

Lincoln Plaza Hotel, 2 Lincoln Plaza, London E14 9BD

Module Leader(s) : Nancy Pire-Smerkanich – DRSc, International Center for Regulatory Science, University of Southern California, USA

Date: Wednesday 20 th November 2019

Time

Activity

Speaker

16.00

Registration

16.15 – 16.30

Welcome & Introduction to Module 12

Nancy Pire- Smerkanich

Module Leader

Nancy Pire-Smerkanich University of Southern California

16.30 – 17.30

Lecture 1: Data Management and Data Governance (DM/DG) • Background, History and Legal Basis o Electronic Data Capture (EDC) o Data Input/Output o Data Querying o Data Management Plans • Data Standards • Regulatory Involvement in DM/DG

Workshop/Activity

17.30 – 18.30

Lecture 2: Document and Information Management • Document Archiving • Registration Tracking • Trial Master Files • Collaborative Authoring

Rohit Malhotra Biogen Idec

Module 12: Data Management and Digitalisation in Regulatory Affairs

Date : Thursday 21 st November 2019

Time

Activity

Speaker

09.00 – 10.30

Lecture 3: Electronic Common Technical Document • Update on Worldwide Use • Current Technical Specifications • Electronic applications forms (eAF) • eCTD Demo • Future version of eCTD

Remco Munnik Iperion

10.30 – 10.45

Refreshment Break

Lecture 4: Regulatory Information, Intelligence and Knowledge Management • RIM Systems and Capabilities • Regulatory Intelligence • Regulatory Knowledge and Management o Administration o Systems

10.45 – 12.00

Rohit Malhotra Biogen Idec

12.00 – 13.00

LUNCH

Remco Munnik

13.00 – 14.45

Lecture 5: EU Telematics Strategy • Update on 2025 Roadmap • Collaboration with EMA and National Has • EMA SPOR •

Iperion

Electronic applications forms (eAF)

14.45– 15.00

Refreshment Break

15.00 – 16.30

Remco Munnik

Lecture 6: Technical Specifications and Compliance • eLabeling and ePI • xEVMPD and ISO IDMP

Iperion

Module 12: Data Management and Digitalisation in Regulatory Affairs

Lecture 7: US Regulatory Requirements • US Data Standards and Resources • CDISC o ADaM o SEND • Reviewer’s Guides • Data Traceability and Accountability • eLabeling - SPL • US FDA KASA System

16.30 – 18.00

Nancy Pire-Smerkanich University of Southern California

Workshop Activity

18.00 -18.30

Date: Friday 22 nd November

09.00 – 10.30

Lecture 8: Data and Document Best Practices and Process • Ensuring Compliance • Role of Regulatory Affairs Professional

Nancy Pire-Smerkanich University of Southern California

Process and documentation workshop

10.30 – 10.45

Refreshment break

10.45 – 12.15

Lecture 9: The Look to the Future • Automatic processing and Data mining (PV and ICSR)

Elspeth Gray MHRA

Machine Learning Artificial Intelligence

• • •

Big Data

RWD/E

12.15 – 13.15

LUNCH

13.15 -15.00

Workshop

Introduction to Module 12: Data Management and Digitalization

20-22Nov2019

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Learning Outcomes

❑ Explain the importance of data, document and information management ❑ Demonstrate a critical understanding of the processes and requirements necessary for completing an eCTD

❑ Critically evaluate the IDMP requirements

❑ Identify issues with electronic compliance

❑ Make recommendations about regulatory information management and IDMP strategies ❑ Critically analyse data and documentation strategies and processes

❑ Critically appraise regulatory processes and documentation

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AGENDA

1. Introductions – who are we? Who are you? 2. Genesis of the course 3. What we intend to cover and what is out of scope 4. How the days will run • Day 1 – Basics of DataM/DG/DocM • Day 2 – Deeper Dives on eCTD, US Reg Requirements, EU Telematics, Technical Specs, RIM1 and RIM2 • Day 3 – Implications and Influencing

Emphasis on content delivery and active learning

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Let’s Get Started

Using the index card provided – please provide between 1-3 questions/topics you want answered/covered.

We will try!

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Data Management and Data Governance

Nancy Pire-Smerkanich, MS, DRSc

Assistant Professor, Department of Regulatory and Quality Sciences,

University of Southern California School of Pharmacy, USA

20-22 November 2019

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AGENDA TOPICS

❑ Data Governance

❑ Background, History and Legal Basis ❑ Electronic Data Capture (EDC) ❑ Data Input/Output ❑ Data Querying ❑ Data Management Plans

❑ Data Standards

❑ Regulatory Involvement in Data Management and Data Governance (DM/DG)

Workshop/Activity

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Data Governance

➢ Data governance is a term that is used for many industries on both a macro and a micro level. ➢ The former is a political concept and forms part of international relations and Internet governance; the latter is a management concept and forms part of corporate governance

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Four Pillars of Data Governance

Data governance is necessary for

compliance with current regulatory expectations for data integrity in pharmaceutical R&D and

manufacturing organizations.

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Four Pillars of Data Governance

Data stewards implement policies in organizations with the goal of increasing data quality. Part of this implementation is “master” data management which evolves based on new use cases and increasing amounts and types of data.

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Data Governance and Quality Systems

➢ Data governance policies have become a regulatory expectation as one of the core quality system policies. ➢ It has been stated by the Medicines and Healthcare products Regulatory Agency (MHRA), European Medicines Agency (EMA), World Health Organization (WHO), Pharmaceutical Inspection Cooperation Scheme (PIC/S), and the Australian government’s Therapeutic Goods Administration (TGA) that a data governance system should be an integral part of the pharmaceutical quality system.

➢ We will come back to this!

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Data Governance/Quality Systems

➢ Per the MHRA, a Data Governance system is the “sum total of arrangements to ensure that data, irrespective of the format in which it is generated, is recorded, processed, retained, and used are complete, consistent, and accurate record throughout the data lifecycle”

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Master Data Management (MDM)

➢ Not unique to pharma ➢ MDM is a method used to define and manage the critical data of an organization to provide, with data integration, a single point of reference. ➢ The data that is mastered may include reference data - the set of permissible values, and the analytical data that supports decision making.

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Critical Data

Various ways to “rank” – by amount, lifecycle, risk 1. GMP data – data related to product quality generated during manufacturing 2. GLP data – data from non-clinical studies and the basis of clinical development 3. GCP data – data from clinical studies, both pre and post marketing, including pharmacovigilance data How would you rank them?

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Critical Data and Standards

1. GMP data – highly regulated but no data standards (excluding stability data – for now) 2. GLP data – CDISC SEND (Day 2) 3. GCP data – CDISC SDTM and ADaM (Day 2)

Let’s start with Data acquisition – specifically clinical data!

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Digitalized Data Acquisition

EDC: An electronic data capture (EDC) system is a computerized system designed for the collection of clinical data in electronic format for use mainly in human clinical trials.

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HISTORY OF EDC

➢ LONG (sometimes painful) history of what began as “remote data entry” (RDE) ➢ Began back in the 1980’s when desktop computers came into existence ➢ Similar situation to US CANDAs where each study had it’s own computer and software ➢ Computers placed at sites where data was entered by clinical study staff and then “sent” to sponsor or CRO ➢ The industry assumed there would be HUGE benefits and accelerated drug development timelines

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Challenges OF EDC

➢

Poor acceptance at sites ➢ Change in process; perceived as more work for Study Coordinators

➢ Same data “cleanliness” issues existed ➢ RDE systems were not intuitive ➢ Glorified paper

➢

No time savings ➢ Time saved at the back end was lost in the front

➢

Technology in its infancy

➢

Not globally feasible

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HISTORY OF EDC

The next 10+ years were spent trying to address site interface and data cleaning methods ● Educate Study Coordinators on process/responsibility ● Programmed edit checks clean data upon entry ● Real time data entry/reporting was achieved Through the use of the internet, data entry at site became data capture for sponsor

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Efficiency of EDC

Over the last decade the use of EDC in clinical trials has become more prominent, with the global EDC systems market estimated to reach a value of almost €935 million by 2025 ➢ In the US the ACA (2010) mandated electronic health records so hospitals were forced to move into all electronic systems ➢ This has not become an automatic or automated data integration but did facilitate eProcessing.

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Data Input/Output Front end: Templated CRF Design

● Information captured during most if not all studies (Demographics, Med History, Phys. Exam, Vitals, etc.) ● Time savings of WEEKS! Middle: Data cleaning/reports ● Real time querying ● Decision making ● Preliminary report/table output Back end: Regulatory Deliverables for countries that require them ● Submission Ready eCRF ● CDISC Compliant Datasets

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Efficiencies achieved

➢ EDC cuts 41% of pre-study preparation time ➢ Use of “standardized” CRFs saves time on both ends of the process ➢ Overall EDC saves on average 30% of the time it takes to conduct a clinical trial ➢ Use of extensive edit checks prevent many incorrect data points from being entered (eg legacy self evident corrections) ➢ Querying can focus on data inconsistencies This is an area where ML/AI will have an impact (Day 3)

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Efficiencies achieved

➢ Integration with other systems can occur ➢ IVRS for efficient randomization ➢ Extraction from electronic health records ➢ Real time output for analytics (eg adaptive designed trials) ➢ Clinical Trial Management Systems (CTMS) which are designed for operational use in clinical trial planning, preparation, performance and reporting.

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BIG Business - Example

➢ Medidata acquired by Dassault Systèmes for $5.8 billion. ➢ Medidata's cloud-based services (data capture and advanced analytics) help with the development of therapeutic innovations and clinical operations performance for pharmaceutical companies, biotechnology firms and others. Jun 13, 2019

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New Problems Emerge ➢ As a result of new technologies and

innovations and electronic record keeping, the volume of information collected before, during and after the clinical trials continues to grow. ➢ LARGE amounts of data ➢ As such, comprehensive data collection and efficient management is now becoming a priority for pharmaceutical companies and clinical research organizations (CROs)

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➢ The Data Management Plan(DMP) is written to define and document the data management tasks, responsibilities, and deliverables for each clinical trial. ➢ The DMP allows the company to proactively assess and plan for the study- specific data management processes, from the receipt of the Case Report Form (CRF) to the study file archiving. ➢ The DMP is based on the clinical trial protocol, the CRF, and the CRF instructions . Data Management Planning and Plans (DMP)

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Data Management Plans

Addressed in multiple US Guidance documents:

Related to Electronic Source Data,

Risk Based Monitoring,

AND

US Dept of HHS, Office of Research Integrity

Which funds NIH funded studies

Addresses data integrity during research process

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Data Integrity

From WHO Technical Report Series No. 996: – Increased observations made regarding good data and record management practices (GDRP) during inspections: – Good manufacturing practice (GMP) – Good clinical practice (GCP) – Good laboratory practice (GLP) regarding data reliability are undoubtedly multifactorial and include

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Data Integrity - Manufacturing

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Data Integrity - Clinical

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Data Integrity Issues

– Failures by organizations to apply robust systems that inhibit data risks, to improve the detection of situations where data reliability may be compromised – Lack of adequate investigation and remediation of root causes when failures do arise. For example: – Validated computerized systems but fail to adequately review and manage original electronic records – Often only review and manage incomplete and/or inappropriate printouts

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Transition by international regulators/Industry to structured content/structured authoring ● Supports more efficient and effective regulatory review ● Supports regulatory science initiatives – Data integrity – Pharmacovigilance (signal detection) – Quality metrics – Risk based inspection scheduling – Mitigate drug shortages – Real World Data/Evidence – In support of benefit/risk assessment Data Matters!

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Per EMA Data Integrity Guidance (2016) – Data integrity enables good decision-making by pharmaceutical manufacturers and regulatory authorities. – Fundamental requirement of the pharmaceutical quality system described in EU GMP chapter 1 – Applying equally to manual (paper) and electronic systems. – “The effort and resource assigned to data integrity measures should be commensurate with the risk to product quality ( risk mitigation ) Data Integrity: Key to Public Health Protection

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• Per Medicines & Healthcare products Regulatory Agency (MHRA)-‘GXP’ Data Integrity Guidance Covers principles of data integrity (ALCOA) – Aims to promote a risk-based approach to data management that includes data risk, criticality and lifecycle. – Data processes (as a lifecycle) to identify data with the greatest GXP impact to determine the most effective and efficient risk-based control for data review and implementation Data Integrity: Key to Public Health Protection

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Per Guidance for Industry: Data Integrity and Compliance with CGMP – FDA has increasingly observed cGMP violations involving data integrity during CGMP inspections – Data integrity-related CGMP violations have led to numerous regulatory actions: – Warning letters – Import alerts – Consent decrees Data Integrity: Key to Public Health Protection

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Data Integrity and Use of Quality Metrics

● Quality metrics are used throughout the pharmaceutical industry: – Monitor quality control systems and processes – Continuous improvement efforts in drug manufacturing ● Metrics can also be used by regulators for the following: – Compliance and inspection policies and practices – Risk-based inspection scheduling of drug manufacturers – Improve the ability to predict and possibly mitigate future drug shortages; – Encourage Industry to implement state-of-the-art, innovative quality management systems for pharmaceutical manufacturing

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“The nice thing about standards is that there are so many of them to choose from.”

-Andrew S. Tannebaum

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The State of Data and Standards Regulatory World View

SPOR Iterative approach to IDMP Falsified Medicines

Structured Product Monograph – SPL Format Utilizing IDMP Data Elements Regulatory Enrolment Process – SPL Format aligning with IDMP Data Elements (future state) eCTD v3.2.2. v4

Directive (FMD) Cross border e- Prescriptions Article 81-EU CT Regulation SPOR/IDMP

PQ/CMC ICSR CDISC Activities Medical Device UDI eCTD v4 *IDMP – Federal Notice*

Medical Device (UDI) ICSR FMD IDMP/SPOR

Data Standards as a Global Issue (Ref: VPerkins

When no Common and Harmonized Data Standards Approach Exists…

• There is no possibility to exchange medicinal product information between regulatory authorities and pharmaceutical industry in a structured and efficient way; • Difficulties in ensuring data consistency in evaluating and comparing medicinal product related information across regions due to the lack of harmonized definitions of terminologies and data sets • Administrative burdens and duplication of efforts requiring substantial human and financial resources to comply with and handle different regional requirements

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Benefits of Government Working with Standards Development Organizations

• Input from international experts: Availability of many experts from various disciplines and countries ➢ Supports regulation/guidance development • Governments can make standards a regulatory requirement ➢ Can result in reduced costs for both private and government entities ❖ More efficient operations ❖ Safety

• World trade ➢ Provides harmonized import/exports requirements ❖ Goods, services, technologies

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Joint Initiative Council on SDO Global Health Informatics Standardization

Formed to enable common, timely health informatics standards by addressing and resolving issues of gaps, overlaps, and counterproductive standardization efforts through: • A mutually agreed upon and used decision process for international standardization needs; • Coordinated standards strategies and plans, with the future goal of making all standards available through ISO; • An integrated work program; and • Focused, specific resolution of overlapping or counteracting standards within the participating SDOs existing work programs

Reference: http://www.jointinitiativecouncil.org/

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FDA Involvement with Data Standards Development Organizations (SDOs)

• International Organization for Standardization (ISO) ✓ Identification of Medicinal Products (IDMP) ✓ Individual Case Safety Reports (ICSR)

Health Level Seven (HL7) ✓ Structured Product Labeling (HL7 SPL) ✓ Common Product Model (HL7 CPM) CDISC ✓ Study Data Tabulation Model (SDTM) ✓ Analysis Data Model (ADaM)

•

•

• International Conference on Harmonisation (ICH) ✓ MedDRA

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FDA Data Standards Strategy & Action Plan

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FDA’s Data Standards Program – Goals

• Support open, consensus-based data standards development

• Utilize a well-defined data standards governance function

• Promote electronic submission of standardized data for regulatory review

• Optimize the regulatory review process to fully leverage standardized data

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Data Standard

➢ A data standard is a set of rules on how a particular type of data should be structured, defined, formatted, or exchanged between computer systems. ➢ There are standards for everything, from how blood pressure is collected to how regulatory materials are submitted electronically to FDA.

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Legal Basis: FDA Safety and Innovation Act (FDASIA) of 2012

Section 1136: Allows FDA to require standardized fully electronic submissions related to marketing applications

• Twenty-four (24) months after publication of the final guidance: New Drug Applications (NDAs) and Biologics License Applications (BLAs) • Thirty-six (36) months after publication of the final guidance: All original commercial Investigational New Drug Applications (INDs)

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Most basis “standard” - XML

XML = Extensible Markup Language

XML (v1.0) currently being used in the following ways: • Current uses • Labeling documents (SPL) • Data Definition Files (DDT) for CDISC SDTM and ADaM data • eCTD Backbones (M1 and M2-M5) • Future Uses • RPS bi-lateral communication (maybe someday) • Clinical protocols (ICH WG)

42

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Communication Processed by RA then disseminated to systems

G-SRS

Molecule Data

API Discovery

Regulatory Affairs/Strategy

Regulatory Data Lifecycle (V. Perkins, Bayer)

SmPC

Specs

Scientific Content Created

RIM

Company Core Data Sheet (CCDS)

USPI

CMC

Labeling

Pre-Clin Clinical

ESG Regulatory Agency

Sponsor

Regulatory Operations

DMS/SharePoint/Fileshare

Compile Dossiers For Submission

Legal

Quality

Supply Chain

Pharmacovigilance

R/B Evaluation

Communications back to Sponsor

Decisions

Assess Content

Use Content for Reports and Correspondence

Evaluation of Product Info (Ad/Promo, Claim

Distribute to Functional Reviewers

ESG Regulatory Agency

Data for Customs or Market Regulators

Regulator

Populate Agency Databases

Validate

Data Needed for Inspectorates

Application Submission Received

Parse & Assign To Appropriate Division

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Regulatory Data Lifecycle (V. Perkins, Bayer)

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If you thought that was scary…

Have you heard of the “Google Effect”?

The experience of forgetting information that you trust a digital device to store and remember for you – Coined by Kaspersky Lab (2015 survey) – 91% of those surveyed (n=1000) utilize the Internet as an online extension of their brain – 44% stated smartphone serves as their memory

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Workshop/Activity

Working in pairs: Can you describe a “use case” for an organization, real or fictional, that relates back to the four pillars of data governance? For example: Data stewardship when acquiring a new company or asset What would this look like – who would handle?

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Document and Information Management

Rohit Malhotra, Senior Director - Biogen

20 th November 2019

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Agenda

Collaborative Authoring

•

Document Archiving

•

Trial Master Files (TMF)

•

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Collaborative Authoring

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System Architecture

Public

4

Confidential - Property of Navitas Life Sciences - 2019

Electronic Document Management Systems

An EDMS (Electronic Document Management System) becomes key for Regulatory Submissions to World-Wide Agencies An optimum document management system makes use of: ● A standardized approach to version control to manage the latest version of all documents

● Approval of documents for inclusion within submissions

● Standard folder structure and metadata for enhanced document storage, search and retrieval

● Rendering technology to automate the creation of document level navigation

● Standardized workflows to streamline the review and approval process

● Metadata capture that can be reused in the submission publishing system

● Standards and processes first prior to system implementation

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Example Document Authoring Process

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Template Best Practices

Content templates can be developed for most of the sections of the CTD. Content templates can include standard headings, instructional and/or boilerplate text and should comply with the organizations formatting standards. Authors should access the latest template when authoring documents so that any template updates can be incorporated.

Using standardized templates can:

▪ Automate the creation of bookmarks (from headings) and some internal hyperlinks. ▪ Ensure all documents are formatted correctly (font size, margins, etc.)

▪ Assist with CTD and granularity compliance

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Standards Best Practice

• Institutionalize a global approach in a “Guidance Interpretation” document that captures document, data, and submission standards • Provide an interpretation of existing guidance and regulations from which internal standards, working practices, etc. are created • Clarify how to address/resolve those areas not clearly defined within the guidance and regulations

• Define the process for deviation

Benefits

● Reduces confusion where guidance is unclear

● Improves delivery of e-submission ready documents

● Establishes global consistency

● Reduces re-work potential

● Increases efficiency

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Sample TOC for document and data standards

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Example Document Workflow

2.7.3 SCE ‐ Final Clinical Study Report 2.7.3 SCE TLG Alignment Meeting + Outline 2.7.3 SCE Update Shell with last batch of Dry Run TLGs 2.7.3 SCE Review 1 2.7.3 SCE MW Updates 2.7.3 SCE Review 2 2.7.3 SCE MW Updates 2.7.3 SCE Team Endorsement 2.7.3 SCE Final TLGS to MW (ISE TLGS Delivered) 2.7.3 SCE MW Updates 2.7.3 SCE Review 1 post final TLGs 2.7.3 SCE MW Updates 2.7.3 SCE Review 2 post final TLGs 2.7.3 SCE MW Updates 2.7.3 SCE Document Quality Review 2.7.3 SCE MW Updates 2.7.3 SCE Leadership approval 2.7.3 SCE Final - Available in Document Management System 2.7.3 SCE Final – Publishing Preparation / Initial QC

2.7.3 SCE Final – Publishing External Link QC / Submission Ready

MILESTONE: 2.7.3 SCE Final Submission Sciences Submission Ready

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Document Process Best Practices

Processes are extremely important in any submission Best Practice Model.

• Documents are created so that they are e-Submission Ready which means:

• Navigation is added upstream in the authoring process which reduces the need to add or correct bookmarks and hyperlinks on the critical path. • Files are formatted correctly before approval which eliminates rework and may automate the creation of certain navigation.

• Standards are utilized to reduce inconsistencies across documents and submissions.

• Functions may rely on document specialists to assist in developing e-submission ready documents.

• Technology such as document management and publishing tools are employed to streamline the submission process. • A strong partnership with IT exists to ensure the technology is configured to support efficient processes and standards.

• Companies take internal advantage of navigational (eCTD) requirements for agencies.

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Document Process Best Practices

Define tasks, roles and responsibilities to support e-Submission Ready standards

● What does the author do? ● What do the formatters do? ● Who reviews what at each step?

Ensure an appropriate, early team review of documents includes a formatting check

● Confirms consistent use of templates and authoring tools/standards

● Addresses formatting considerations early in document development

● Establishes focus toward submission ready standards for content and format

Benefits

● Improves delivery of submission ready documents ● Establishes global consistency ● Reduces re-work potential

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Example Author QC checklist

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Example Formatting QC checklist

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Hyperlink Best Practices

• Internal and cross-document hyperlinks assist agency and internal reviewers in navigating the content of a submission. • Because authors know the most about the supportive information and where they want a reviewer to go, they are typically the most qualified person to identify and confirm hyperlinks to ensure they take the reviewer to the correct destination. • When hyperlink creation is pushed to the end of the submission process, it creates more work on the critical path and the potential for mistakes. • By building hyperlinks upstream (in the authoring process), there is less of a chance that the hyperlinks will be broken or point to an incorrect location

• By building hyperlinks upstream (in the authoring process), there is less of a

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Collaborative Authoring Keys to Success

• Define submission ready criteria/standards to include content as well as format • Define and implement document authoring process(es) with standard tasks and clear responsibilities to improve efficiency and eliminate unnecessary hand offs • Consistently apply submission ready criteria/standards across all submission document types independent of submission output • Define reviewer responsibilities in document authoring process versus submission process

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Document Archiving

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Evolution

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Purpose of Archiving

In theory records being retained and maintained allows

• Reconstruction of study, trial, process or procedure

• Facilitating information and results generated to be verified

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Guidance

Retention & Archiving of Study Materials & process records, raw data & source data critical part of compliance and regulatory Compliance

• Good Laboratory Practice (GLP)

• Good Clinical Practice (GCP)

• Good Manufacturing Practice (GMP)

Pharmacovigilance (PV)

•

• 21CFR Part 11 – electronic records & signatures

Financial requirements

•

• Other business critical needs..

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Implications of transition from paper to electronic Compliance of archiving of electronic records no different to paper requirements but different procedures

• Secured – designated archive area within a system or migrated into a dedicated archive repository • Metadata/electronic signatures need to be maintained along with records • Access limited to designated individuals Electronic Records should be archived in such a way to ensure their reliability, integrity and usability at all times

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Roles and Responsibilities

Archivist – accountability to ensure records are protected, controlled and managed to maintain integrity and validity and accessible to regulatory authorities when required

IT Staff

• Supporting computer software, hardware and IT infrastructure

Automated regular backups

•

Ensuring “chain of custody”

•

Systems validation

•

• Facilitation of storage and retrieval of records • Access control to archive and archive records • Documented training in how to operate an electronic archive

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Archiving of electronic records

• Decision made prior to creation of records • Validation of system • Standard Operating Procedures (SOPs) • Equipment used for generation, processing & retention – reliable and accurate • System validation • Audit trails – for alterations, modifications and corrections • Metadata - context

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Types of Electronic Archives

Defined Archive Area

Designated Archive System

• Physical separation from non-

Single or multiple systems depending on company computer applications • Specific applications per archive appropriately documented

•

archive records or virtual separation via metadata

• Archived records will be locked to avoid alteration or deletion and under control of Archivist

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Portable Media

• Treated same as hard copy in physical records

Floppy Disc

•

DAT Tapes

•

Media degradation…

•

Compact Cassettes

•

Poor search and retrieval capabilities

•

Magnetic Tape

•

DVD/CD Optical Disk

•

External Hard Drives

•

Flash Drives

•

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Electronic Record Preservation –Challenges & Risks

EU GMP “Secure controls must be in place to ensure integrity of the record throughout the retention period & validated where appropriate”

Media degradation

•

Media Obsolesce

•

Hardware Obsolesce

•

Software Obsolesce

•

Preservation Strategy

•

• Future Proofing – Cloud based solutions

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Resources

GAMP 4 Recommended Environmental Conditions for Storing Various Recording Media

Association for Clinical Data Management (ACDM), Computer Systems Validation in Clinical Research - A Practical Guide (Edition 2, 2004)

GAMP Good Practice Guide: Electronic Data Archiving, ISPE, July 2007

Digital Preservation Council’s Technology Watch on File formats.

ICH Harmonised Tripartite Guideline for Good Clinical Practice E6(R1), CPMP/ICH/135/95/Step5, 1996

EU Commission Directive 2005/28/EC of 8 April 2005,laying down principles and detailed guidelines for good clinical practice as regards investigational medicinal products for human use, as well as the requirements for authorisation of the manufacturing or importation of such products

ISO 11799: 2003(E) Information and documentation — Document storage requirements for archive and library materials. ISO 14721:2012 Space data and information transfer systems -- Open archival information system (OAIS) -- Reference model

EudraLex The Rules Governing Medicinal Products in the EU, Volume 4 GMP,Chapter 4: Documentation

ISO 15489-1:2001 Information and documentation -- Records management

FDA Draft Guidance for Industry: Electronic Source Documents, December 2010,UCM239052

ISO 16363:2012 Space data and information transfer systems -- Audit and certification of trustworthy digital repositories ISO 19005-1:2005 and ISO 19005-5:2010 Document management. Electronicdocument file format for long- term preservation (the PDF/A standard)

FDA: 21 CFR Part 11; Electronic Records; Electronic Signatures Rule.

FDA: 21 CFR Part 211 Current Good Manufacturing Process for Finished Pharmaceuticals

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Resources

ISO/TC 46/SC 11 Digital Records Protection: Where to start guide. Understanding the issues specific to the preservation of digital records. Development of a preservation plan. Safeguarding digital records over time with confidence. MHRA UK Medicines and Healthcare products Regulatory Agency (MHRA). Good Laboratory Practice - Guidance on Archiving. March 2006. OECD GLP Principles. OECD Series on principles of Good Laboratory Practice and compliance monitoring, Number 1. ENV/MC/CHEM(98)17 OECD Series on Principles of Good Laboratory Practice and Compliance Monitoring no. 10: GLP Consensus document “The application of the Principles of GLP to Computerised Systems”

OECD Series on Principles of Good Laboratory Practice and Compliance Monitoring no. 15: Establishment and Control of Archives that Operate in Compliance with the Principles of GLP (published in 2007). SAG Scientific Archivist Group. Guidance on the archiving of Good Clinical Practice material. ISBN 978-0- 9557659-0-2

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Trial Master Files (TMF)

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What is the TMF?

• The TMF is a collection of records that tells the story of a clinical trial • A properly maintained TMF ensures all actions that occurred and decisions that were made during the trial can be reconstructed • Ensures audit and inspection-readiness at all times, but also allows regulatory authorities to evaluate the quality and integrity of the trial data

• The TMF should be a stand- alone set of records

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Guidance

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Guidance

EMA –Draft Guideline on GCP compliance

• Provides clear guidance on how inspectors want to access eTMF • Provides inspection requirements for eTMF systems • Provides guidance on destruction of paper records (certified copies)

• Requires that TMFs be up to date at all times

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TMF Process Flow

Manage Sponsor File Throughout trial

Initiate Sponsor File

Close Out TMF

Conduct Final Completeness and Accuracy of TMF

Collect and File Records in Sponsor File Within Given Timelines

Initiate Sponsor File Initiate Using List of essential elements

Communicate List of Trial Related Expected Records

Apply Good Document Practice for all Records

Move TMF to Archive

Remediate Issues

Conduct Completeness and Accuracy of Sponsor File

Report on Status of Sponsor File

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TMF Requirements

The TMF:

• May be paper-based, electronic (eTMF), or a combination of both

• Contains content that supports the trial and helps reconstruct & evaluate the trial conduct

• Is maintained both at the sponsor and at the investigator sites

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Where is my TMF Content?

What is considered to

Identify what Content is being held in which system

Identify which system holds TMF relevant information

be TMF Content

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How is a TMF Organised

Zone

Section

Artifacts

1.

Trial Management

Each Section is further defined into artifacts

Each zone contains specific sections that are standard by the industry

2.

Central Trial Documents

These documents can be defined specific to the company processes

3.

Regulatory

Generalized topics

4.

IRB/IEC and other Approvals

5.

Site Management

Documents can be blinded or unblinded

6.

IP and Trial Supplies

7.

Safety Reporting

Core TMF documents are required per industry standard

8.

Centralized Testing

Recommended TMF documents are suggested per the industry

9.

Third Parties

10.

Data Management

11.

Statistics

DIA TMF reference model v.3

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Emails – why are they important?

Email correspondence can be an important component in reconstructing the trial conduct

From MHRA TMF FAQ Page:

● “Relevant correspondence that is necessary for reconstruction of key activities and decisions (for example the medical monitor allows an ineligible subject to remain in the trial) or that contains other significant information must be retained.”

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Example TMF Team and Governance Structure

Study Management Team Functional TMF Core Team Functional TMF Council

• • • •

Quality Council

• Quality & Compliance Executive Committee

• Collaboration across many functional areas • Numerous roles are responsible for creating, collecting, reviewing, approving and managing the TMF Content

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Not regulated so Company set Service Level Agreements

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Example Industry Metrics

Quality

Completeness

Timeliness

% of artifacts that meet quality standards % of artifacts that have had queries or modifications

% of documents present that are expected at a given milestone or timepoint

•

•

Time to set up TMF

•

Time from finalisation to document uploaded into TMF Time from upload to QC completed

•

•

•

% of documents without issues

•

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Electronic Trial Master File – Exchange Mechanism Standard - DRAFT

• Defining a standardized and simple mechanism for transfer of eTMF Content (similar in approach to eCTD and CDSIC standards)

Content Export + XML

•

• Envisaged to allow the exchange of artifacts or information between different systems could be automated • Archiving of eTMF Content • Use within Mergers/Acquisitions • Transfer from eTMF content from CROs to sponsors

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Resources

• in relation to trial master file (paper and/or electronic) for content, management, archiving, audit and inspection of clinical trials -Public consultation finished in July 2017 • International Conference on Harmonisation Good Clinical Practice Guidelines (ICH E6) • United States (US) 21 Code of Federal Regulation (CFR) 312 • European Union (EU) Clinical Trials Directive and GCP Directive (2001/2/0/EC and 2005/28/EC) • EMA/15975/2016 • EMA Recommendation on the content of the Trial Master File and archiving July 2006 • Clinical Trials Regulation (No. 536/2014)

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In Conclusion

If you think architecture is expensive, try bad architecture – Brian Foote

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eSubmission

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Remco Munnik

• 20+ years industry experience with focus on submission procedures

• Since 2007: Direct contact with EMA and EU NCAs Chairman of Medicines for Europe working group for Telematics/eSubmission

o eCTD, eAF, CESP, Harmonization and more… o IDMP IWG, xEVMPD, P(roduct) and O(rganisation) group

• Since July 2019: Associate Director Iperion

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IPERION is a life sciences consulting and services company, with global presence and support

US Office (2018)

EU HQ Office

JP Office (2020)

Support 20+ clients. Focus on Top 100 Pharma, but also regulators and standardization organizations

Aiming for establishing a “trusted advisor relationship”

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Confidential – IPERION ® 2019

3

Our drivers A strong common basis for successful partnerships

Change the industry by increased interoperability using standards

Increase efficiency and speed of introduction of medicines

Increase the accessibility and accuracy of product information leading to better

use

Rebalance the attention from admin tasks towards value added activities at both

industry and regulators

Reduce duplication of activities at regulators through interoperability, common

process design and concentration of knowledge

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Confidential – IPERION ® 2019

4

Regulatory Intelligence & strategic advice using our extended network, best practices and industry experience

EMA

SPOR (IDMP) Taskforce

Industry Reps

IDMP roundtable

NEN / ISO

Industry clients

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Confidential – IPERION ® 2019

5

eCTD

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CTD – Common Technical Document

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Slide 7

CTD – Common Technical Document

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Slide 8

eCTD eCTD = Electronic Common Technical Document

An eCTD application is a CTD application, but then electronically.

Electronically means for eCTD: • Complete dossier in electronic format • XML files (XML backbone) • Specifications followed for the Granularity, folder- & filename convention of the dossier • Navigation through the dossier by means of hyperlinks and bookmarks

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Slide 9

Global eCTD Status

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Electronic Submission Terms

eCTD

ICH- E2B

NeeS

SPL

EVMPD

ISO IDMP

Gateway

HL7 RPS

eAF

Central Reposit ory

CESP

PIM

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Slide 11

History of eSubmission in EU

2005: HMA end 2009 acceptance of eCTD only in EU 2008: NeeS mandatory in some countries 2010: EMA implements eCTD only for CP November 2011: TIGes discussion for the need of clear guidance on the future of eCTD and eSubmission

ROADMAP!!!!

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Slide 12