Achieving continual inspection readiness

Achieving Continual TMF Inspection Readiness
A metaTMF approach to ensure preparedness and compliance

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Agenda
• Inspection trends and perspectives
• The issues in TMF rescues
• The keys to continual inspection readiness
• Realizing efficiencies from metrics and governance
• The value of assessing metaTMF maturity

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TMF Inspections:
Trends & Perspectives

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Poll Question #1
On average, how long does your organization prepare
for one clinical trial inspection?
A. Less than 1 month
B. 1 - 3 months
C. 4 - 6 months
D. 7 - 12 months
E. More than one year

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Critical Factors: What Do Inspectors Expect?
Regulations for Trial Master File and Electronic Systems Unchanged
• Valuable insight from TMF guidance and reflection materials
EMA GCP Inspectors Working Group, TMF Reflection Paper, 2013
MHRA Good Clinical Practice Guide, Chapter 10, Trial Master File and Archiving, 2012
• Do they inspect paper or electronic?
‒ “The inspectors must have direct access to the entire TMF…which means reviewing the TMF as used by
the staff conducting the trial.” EMA Reflection Paper
• Overview follows, grouped in three categories
‒ TMF management principles – both paper and eTMF
‒ Expectations for inspection – paper and eTMF
‒ eTMF insights
• And….what about ISF (investigator site file)? And eISF?

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What Do Inspectors Expect?
General TMF Management - Paper and eTMF
Content Management
• Content robust
• Version control
• Timely filing
• Subject protected
Process Controls for Each TMF
• CRO oversight
• Consistency
• Quality assurance
• Location and chain of custody
TMF Inspection enables full reconstruction of the trial
Holistic Organization Controls
• Full lifecycle - creation to archive
• Effective structure
• Controlled access
• Investigator’s file
• Availability

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TMF Inspection Preparations
• Duration
• Access
• Ease of use
• Visibility
High value TMF programs routinely conduct mock inspections

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eTMF Systems
eTMF System Controls
• Security
• Training
• Access
• Audit trial
eTMF Content Clarity
• Metadata
• Naming
• Scanning
• Locking
• Workflow approval
eTMF System Processes
• Validation
• Back up

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MHRA
April 2013-March 2014
• +50% of sponsors inspected had at least one Major and/or Critical finding
• Highest percentage of major findings - Record Keeping/Essential Documents
April 2014 - MHRA moves TMF up into the Critical GCP Category
“Where provision of the Trial Master File (TMF) does not comply with Regulation 31A 1-3, as the
TMF is not readily available or accessible, or the TMF is incomplete to such an extent that it
cannot form the basis of inspection and therefore impedes or obstructs inspectors carrying out
their duties in verifying compliance with the Regulations.”

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Inspection Statements About eTMF Failures

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FDA
• The FDA’s regulations do not identify a Trial Master File
• BIMO inspects “practices and procedures” of sponsors, CROs and monitors
• BIMO Compliance Program Guidance Manuals identify scores of expected content types,
and are freely available to assess for TMF content alignment
• FDA inspectors are keenly interested in oversight
‒ In 2013, sponsor received warning letter for a CRO outsourced trial where the CRO was not sited:
the sponsor held responsible to ensure the trial was conducted per GCP
• Change is at hand! FDA department realignments announced December 2014, increased
focus on Quality by Design (QbD), alignment to risk-based approaches, and interest in KPIs /
metrics

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What to Expect in TMF Inspection?
• TMF review methods? Anything, and everything
• Inspectors are human, each with unique histories and preferences
• Inspectors are sharing perspectives, processes and insights across the globe
• Inspectors are public servants whose operational methods are available to the public
• To increase likelihood of intense scrutiny, extended duration and poor outcomes:
• Surprise the inspector with problems when they arrive
• Make it difficult to comply with his or her preferred method
• Ignore the publically available inspection checklists / manuals
• Don’t have the initial “always asked” content readily available
• Rather than answer “will find out” if unknowns, prevaricate
• Inspectors know trial teams are human too. The TMF needs to tell the story of team’s adherence to
good clinical practice, not perfect clinical practice.

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New TMF Acronyms!
No inspection controls Full inspection controls
Titanic Monetary Fine
Terrified Manager’s Fougasse
(fr=landmine)
Total Major Finding
extra
Terrifically Managed Forever

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Perspective…
“In life, unlike chess, the game continues
after checkmate.
- Isaac Asimov
Fantastic Voyage II: Destination Brain (1987)
”

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The Problem with TMF Rescues
Rational: Majority of Trials Fail, So Wait for TMF Quality Rescue
• Record keeping is required in all trials, whether or not successful endpoints
• Delays in producing TMF components increase inspector irritation and scrutiny
• Critical baseline content gaps raise eyebrows and decrease credibility
TMF 101 – maintain a solid pathway for CVs, training records, org charts and SOPs
• Too often, original team who could fill the gaps are long gone
• Extensive Notes-to-File documenting content gaps confirms inspector concerns
The trial story remains undocumented

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The Expense of TMF Rescues
Rational: TMF Rescues are a Necessary Evil
• The internal manpower and time spent on internal TMF rescues are company energy assets
better applied to the gas-guzzling engine of new product R&D
• The expensive of outsourcing TMF rescue is massive
TMF 101 – simply scanning and uploading a paper TMF does not increase security, surety or
inspection readiness; it is, however, quite costly
• TMF rescue, performed by motivated and dedicated resources, will deliver quality
conclusions, not surety for inspection success

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Unlock! The Keys to
Continual Inspection Readiness:
Information Architecture and TMF Responsibilities

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Every idea I've ever had
I've written down, and it's
all there on paper. And I
won't be gone; it'll be there.
- Isaac Asimov
'Isaac Asimov Speaks' ,
The Humanist (Jan/Feb 1989)
”
“

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Continual Inspection Readiness = TMF Accountability
Trial TMF Owner ensures all team adheres to mission: any day, everywhere, ready for inspection
• My team understands what’s expected and why
• My team agrees to the timeliness and quality SLAs
• TMF Quality and Completeness is my job
• My team has enough training and time to effect the change
• My TMF is started, managed, finalized and locked in a timely fashion, per my TMF Plan
Trial Team Contributors owns inspection readiness responsibilities
• I know my content is required in the TMF (and what not to file)
• I file my TMF content as soon as it’s ready
• My TMF content is complete and accurate
• I am responsible for my content’s quality
• My job description and annual goals include TMF responsibilities

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Continual Inspection Readiness = TMF Accountability
All Trial team members confirm TMF Completeness
• All notes-to-file replaced with single issue / action / resolution logs
• Periodic standing meeting on issues log with trial history documentation confirmation
• TMF quality reviews are scheduled, completed and closed
• TMF penultimate completeness review is completed before team disbands
TMF Support Squad detects signals, supports improvements
• Executes TMF Owner’s Plan for assessment of timeliness, quality, accuracy
• Ensures CAPAs with Trial TMF / Process Owner when signals exceeds baseline
• Regularly passes mock inspection drills
• Aligns with Quality Organization for audits and inspections
TMF Process Owner owns achievable, meaningful and actionable metrics
• The buck stops here for TMF Governance, informed by data

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The Framework of metaTMF
PEOPLE
PROCESS
eTMF
IRT, EDC, ePRO…
Safety, CTMS, RIM…
Portal…
Plan and Execute
Examine and Govern
Repeat
All content required for trial inspection
metaTMF
Management

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What is metaTMF?
metaTMF is aligned, accurate and accountable Information Architecture, with holistically
governed components of people, process and tools
Enables continual inspection readiness
• Content tells trial story, proves compliance to GCP, on time, ready for inspection
Enables next gen, risk-based clinical process enablement
• Leverages all trial enablement signals derived from TMF content
• Detects TMF quality issues in real time risk-based approach
Governance and metrics to confirm and improve TMF Program
• Health and value of the program, and tools and each TMF

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Poll Question #2
How many rows is your TMF content list / TMF index today?
A. 200 or less
B. 201-400
C. 401-600
D. 601-800
E. 801+

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Paragon Information Architecture (IA) Approach
TMF Master List
•Holistic definition and scope of
TMF content (regardless of
repository)
•Identification of all artifacts
needed for a Health Authority
Inspection
•Built from legacy artifact
inventory, TMF Ref Model, SOP
review and discussions with
trial team experts
Systems of Record
•Identification of other systems
(not eTMF) that house content
(for ex, stats environments)
•Identification of content that
will link or copy to eTMF, with a
lens to collaboration,
authoring and access
requirements
•Plan for governance of TMF
Master and Systems of Record
(who, where, commitment for,
annual review)
eTMF Index
•Content that will be managed
(created, uploaded, versioned,
etc) in the eTMF
•Includes future state content
clarity
•Identifies team role responsible
for content (content steward)
•Details specific content
requirements such as special
security.
•Accounts for any vendor
required differences
eTMF Data Architecture
System implementation specific
details such as:
-Metadata
-Content types
-Placeholders
•eTMF Data Architecture
informs the system
Configuration Specification

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All records required for TMF Inspection
TMF Master List precedes
System of Record …
TMF Master List
• Leverages industry standards refined
to organization specificity
• Includes best practice
recommendations
• Opportunity to reduce record burden
(trackers, signature pages, etc.)
• Includes content identified in trial
related SOPs and trial practices
• Drive to a new corporate TMF clarity
(TMF boundaries beyond clinical)
TMF Master List
Current TMF TOCs
Other Trial Records
(SOPs and practice)
TMF Reference
Model
metaTMF Information Architecture (1 of 3)

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Systems of Record
• For each TMF Master List artifact, details
what system of record stores content – eTMF
or other
• Maintained within Master - serves as map for
both active TMF improvements and future
inspections
• eTMF index reflects the needs of the “daily”
core TMF community – monitors, managers,
site personnel
Why not all records in eTMF? Other systems
are vital to smoothly support different trial
processes (Safety, IRT, EDC, etc.)

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eTMF Index clarity is required for system configuration
Additional eTMF detail that enables the “miracle of metadata” for eTMF inspection readiness:
enables workflow, reporting, required / missing content indicators:
• Content steward / accountable party
• SOP and template relationships
• Translation requirements
• File level and ISF relationship
• Date conventions and expiry
• Workflow for approvals and milestones
• Therapeutic and Country specifications
• Special Security
Trial/County/Site Level Template Expires Translation required Special Security Approval type Milestone

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Poll Question #3
What section of your TMF do you have the least confidence
would pass an inspection?
A. CRO/Vendor Oversight
B. Health Authority Documentation
C. Safety Documentation
D. Significant Trial Decisions
E. Trial Team Qualifications (CV/Training)

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Governance + Metrics =
Compliance + Efficiencies

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eTMF in Perspective
“Part of the inhumanity of the computer is that,
once it is competently programmed and working
smoothly, it is completely honest.
- Isaac Asimov
Change! (1983)
”

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Governance and Metrics
Complete
Concurrent
Quality
TMF Transparency confirms inspection readiness
and efficiencies
Complete – TMF will allow reconstruction of the
trial and demonstrate GCP compliance
Concurrent – real and timely data confirm record
collection parameters are meeting SLAs
Quality – people execute processes consistently,
building confidence in data

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TMF Metric Types
TYPE DEFINITION
Administration Indication of whether TMFs have defined ownership and
planning measures in place
Completeness Extent to which a TMF contains all documents expected
by a specific point in the study
Quality Measure of whether document content, metadata, and
indexing are complete and accurate
Timeliness Indication of whether documents are available when
expected/needed and of how long documents take to
finalize
Use Measure of how frequently an electronic TMF system is
accessed
Volume Measure of the types, numbers, and sizes of documents
in a TMF
Adapted from – TMF Reference Model, Metrics Subteam

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Governance Drives Maturity
People
• Clinical Operations
• Drug Safety
• CROs & Vendors
• Sites
Processes
• Upload/Indexing
• Study Management
• Inspection
Readiness
Technology
•eTMF ECMS
•Clean Data interfaces
• Command center for
all trial collaboration
Measure People
• Driving adoption is key for meaningful engagement
with all stakeholders
• People keep TMFs inspection ready, not systems
• Cross-functional complexities must be addressed, up
front and all roles clearly defined with target metrics
Measuring Process
• Transparent process adherence needed for inspection
surety and value
• Global harmonization and process simplification is
required to realize efficiencies
Measuring Technology
• Solution adoption is 100% dependent on the
alignment of people and processes with system
configuration and functionality
• An agile, iterative approach, driven by business
feedback, enables long-term viability and adoption and
proves value

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metaTMF:
Stages of eTMF and
TMF Maturity Model

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Poll Question #4
What is your biggest gap in TMF Management today?
A. Tools
B. Information architecture
C. People
D. Governance
E. Process

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TMF in Perspective
“Life is pleasant. Death is peaceful. It's the
transition that's troublesome.
- Isaac Asimov
Fantastic Voyage II:
Destination Brain (1987)
”

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Stages of eTMF Maturity
Karen, the eTMF stages slide
Archive
Active
Integrated
Archive eTMF
• Electronic archive of TMF
documents
• Easier access for
business users
• Standardized TMF
structure and
management
• Centralized management
and maintenance
• Well managed, AFTER
document completes
business process
• Minimal transition from
paper to electronic
documents
• Strong Scanning /
Indexing reliance
Active eTMF
• eTMF drives business
processes
• Business users rely on
eTMF for all content needs
• Structure flexibility for trial
requirements
• Improvements driven by
central metrics
• Doc mgmt DURING
business process (i.e. IP
Release Authorization)
• Clin Systems integration for
consistent metadata
• E-workflow for internal
review / approval
• Moderate transition from
paper to e-docs
Integrated eTMF
• Process and user
integration with site for
full electronic submission
/ review
• Inspection readiness
embedded in all eTMF
user behaviors
• Process-driven trial
milestone completion
• Full integration with
internal systems
• All documents signed
electronically (digital
signatures), with legal/reg
exceptions
• Transition from managing
documents to managing
data

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TMF Maturity Model Delivers the Full Picture
* Maps the level of
sophistication of TMF
Program for process,
collaboration, governance,
transparency
* Benchmarks maturity
against industry, and
clarifies program targets
* Calculates TMF Program
gaps and identifies areas
of critical focus
* Deep dive on specific,
targeted topics assessing
current state effectiveness
* Uses current data on
industry and best practice
objectives to guide risk-
based prioritization
* Visibility to specific gaps
and mechanism to assess
impact on critical path to
business drivers

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TMF Maturity Model Detail
Criteria are organized in four topics: Organization, Process, Tools/Templates, eTMF system
Topics contain detailed assessments of items such as:
• Organization: Compliance, Executive Support, Training
• Process: Access, Controlled Storage, TMF Roles
• Tools: TMF Skills Assessment, TMF Manual, Standard Reports
• eTMF System: Application Integration, Metadata, Security
Each item in the topic is assigned a value between 1-5 for:
• Weight– value of the item to TMF program maturity
• Current State Score– where the organization scores today
• Best Practice– what is achievable in a fully mature model
• Industry Benchmark– where the industry is today
• Goal State– desired goal state for the TMF program
• Project Analysis –details / notes on current state where required
Results are calculated and reported by topic, presented as Prioritization Scores, with insight on
critical gaps and requirements

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TMF Maturity Model Process
Identify Assess Score Confirm Apply
User Requirements
Use Cases
Current State
Future State
Gap Assessment Governance
Questionnaires
Interviews
Scoring Spreadsheet TMF Program ManualPresentation

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Current
Managed/Defined
Maturity State Current Maturity
• Standardize full TMF to encompass…
• Centralize eTMF repository…
• Centralize active eTMF capability …
• Standardize vendor approach globally …
• Identify dependencies with strategic
initiatives…
Future
4
Target Maturity
Compliance:
• Gap in full TMF….
• Inspection preparation…
• Vendor oversight …...
• Vendor practices vary….
Organization
• Reorgs and leadership changes….
• No full TMF…
2.2
TMF Maturity Assessment: Organization
Average Current
State
Average
Industry
Benchmark
Average Future
Goal State
Average Gap
Organization 2.20 3.00 4.06 1.80
Processes 3.70 2.48 4.32 0.61
Tools and Templates 3.35 2.12 4.00 0.65
eTMF System 2.48 2.73 4.16 1.57
Qualitatively Managed

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Current
Initial/Managed
• Fully meets the TMF use requirements…
• Centralized control supports security…
• Standardize process interactions with vendors
…
• Consistent, periodic review for full TMF…
• Reduced compliance risk…
• Consistent business processes and
responsibility..
Future
4.3
Target Maturity
TMF Records Access
• Gap for vendor and full TMF…
• Collaboration tools risk…..
• Dependence on convenience copies…
• Chain of custody not controlled ….
Process Consistency
• Archive and retention management not
mature…
• Issue tracking…
• TMF resource planning….
1.6
TMF Maturity Assessment: Processes
Average Current
State
Average
Industry
Benchmark
Average Future
Goal State
Average Gap
Organization 3.59 3.00 4.06 0.47
Processes 1.60 2.48 4.30 2.70
eTMF System 2.48 2.73 4.18 1.57

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Current
Defined
• Standardize roles and include responsibilities in
annual reviews…
• Consistent, transparent process…
• Local document upload
• Establish a global TMF Plan process…
• Link Templates…
• Standard global tracking…
Future
Maturity State
4
Target Maturity
Tools
• Job descriptions and expectations…
• TMF Service Support Roles….
• No single resource….
• TMF management is not targeted…
• TMF Plans only created for CRO…
Templates
• Templates not in eTMF….
• No dashboards….
3.4
TMF Maturity Assessment: Tools & Templates
Average Current
State
Average
Industry
Benchmark
Average Future
Goal State
Average Gap
Organization 3.59 3.00 4.06 0.47
Processes 3.70 2.48 4.32 0.61
eTMF System 2.58 2.73 4.16 1.57

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Current
N/A
• Integration with systems to exchange data and
documents…
• E-workflows for review / approval /
eSignature…
• Streamline content creation/upload..
• Smart Metrics in real time…
• Structure flexibility for trial requirements…
• Global Language…
• Periodic mock inspections….
Future
4.2
Target Maturity
• eTMF is passive repository…
• Integrations limited….
• Workflows eSignature not used…
• Multiple tabs for metadata…
• Study reporting limited to Excel…
• No alert mechanisms
• No study-specific structure creation…
• No multiple character-sets and languages…
• eTMF functionality underutilized…
• Mock inspection gap….
2.6
TMF Maturity Assessment: System
Average Current
State
Average
Industry
Benchmark
Average Future
Goal State
Average Gap
Organization 3.59 3.00 4.06 0.47
Processes 3.70 2.48 4.32 0.61
eTMF System 2.48 2.73 4.16 1.57
Managed / Defined

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TMF Maturity Overall Results
Visible
Issues
Underlying
Issues

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Closing thoughts
Systems are key to efficiencies and speed to transparency and cannot solve for
continual TMF inspection readiness
• Continual TMF Inspection Readiness is all about the base
‒ Effective team participation with actionable Information Architecture
• TMF Maturity and Governance matters
‒ Identify and solve the targeted problems
‒ Measure and repeat
• Until regulations change, stay active on inspection perspectives globally, and test your
parameters to the toughest guidance
‒ Ensure your mock inspections can pass muster

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Watch the first webinar in this series:
“How To Deliver Clinical Process Enablement
Through metaTMF Management”
http://hubs.ly/y0td4m0
f r o s s @ c o n s u l t p a r a g o n . c o m k m s c h a u @ c o n s u l t p a r a g o n . c o m

Achieving continual inspection readiness

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