Working in an Electronic World - How to

Working in an Electronic World - How to
Make a Smooth Transition to an eTMF
By Jennifer Goldsmith
We live in an electronic world today.
We shop online rather than at the mall.
We deposit checks via mobile device
instead of a drive-up window. We talk
through video-chat instead of sending
letters. As consumers, we have largely adjusted to
these changes and reaped the rewards—increasing
our efficiency, becoming more productive, maintaining closer relationships with distant relatives.
As professionals, however, we haven’t all adapted
as smoothly. Nowhere is this truer than in life sciences, especially in the clinical development setting, where most organizations are already working
in an electronic world but still thinking in “paper.”
Often, the workflow follows paper principles but
gets shared and captured in electronic format, resulting in redundancies and inefficiencies.
Clinical trial sponsors have much to gain from
going electronic—from cost reductions and improvements in trial efficiency, to increased compliance and reduced cycle times.1 With the costs
of conducting clinical trials reportedly increasing
60 percent compared to just five years ago2, many
life sciences companies are re-engineering clinical
study processes to take advantage of the electronic
world in their determination to improve the quality
and efficiency of their trials.
One of the major cost drivers is the mismanagement of trial documentation. According to a recent
report by McKinsey & Company, “a 12-month delay
in product approval due to improper management
of clinical trial documents can increase development costs by tens of millions of dollars and drive
significant lost revenue on the order of $1-2B dollars for a blockbuster product.”3
Without a doubt, life sciences companies deal
with a huge regulatory and operational burden to
maintain the trial master file (TMF), and in many
cases, the move to an electronic TMF failed to deliver the desired results. This article assembles the
latest research and expert advice on how to transition successfully when adopting an eTMF.
Learning from industry: Common mistakes
Many life sciences companies are stuck between
paper and electronic.5 In fact, 48% of sponsors rely
upon hybrid systems that combine paper-based
and electronic processes, according to the lastest
TMF Reference Model survey.6 Such hybrids often
store some electronic documents, but are fundamentally static systems or fileshares for housing
TMF documents.
“These ‘pseudo-eTMFs’ may contain an electronic
element, but they aren’t effective in the long term
because, fundamentally, they are built around a
paper framework. Even if the documents are stored
electronically, they are exchanged using paper or
email,” said Susan Nakayama, a pharmaceutical trials management consultant presenting at a recent
eTMF Roundtable event.
Donna Dorozinsky, president of DWD & Associates, a clinical research consulting and training
firm that supports pharmaceutical leaders such as
Abbott Laboratories, Bristol-Myers Squibb, Clinilabs, and Parexel International, added, “Companies
are already living and working in an electronic
world but they haven’t had time to fully transition
to paperless processes, so they have created bandaids. Many already have an electronic Clinical Trial
Master system (eCTMS), for example, but still use
a paper TMF. Or, some leverage document management systems that are not Part 11-compliant or
An eTMF application can elevate business processes and lead to better clinical trial execution.
In fact, according to a 2013 survey of life sciences
companies titled “The State of Trial Master Files,”
respondents cite increased productivity, reduced
time to prepare for study milestones and improved
audit results most often as the key benefits of adopting an eTMF.7 Understanding the potential benefits
is important to setting the correct expecations for
changes to processes and systems. For example, establishing a clear organizing structure by using the
DIA TMF Reference Model helps users know where
to place TMF documents, and an eTMF’s innate rich
metadata and search capabilities also helps users
address one of their most important concerns: the
need to locate documents quickly.7
“One of the most common responses that we get
from clients who are now fully transitioned to an
eTMF is ‘we can find things now and what we find is
complete and inspection ready,’” said Dorozinsky. “In
the past, clients filed a compound but still had an
incomplete TMF for their pivotal studies, resulting
in significant challenges during regulatory inspections. With an eTMF, documents are readily available,
quality-checked, and all in one place so gaps can be
easily identified and quickly corrected. It’s a huge
timesaver and can provide a competitive advantage
when racing to get a new therapy to market.”
Designing the system: Where to focus
Making the most of an eTMF requires technology
and processes that bring people to the documents
instead of documents to the people—this is a fundamental difference from how things are typically
handled today. According to a recent survey of 250
TMF business owners, the two most common ways
to exchange TMF documents between a sponsor
and a contract research organization (CRO) are
email and physically shipping paper. The reported
use of email at 68% was greater than the use of
structured mechanisms like content management
systems (29%) and eTMF applications (15%) combined.10 Both email and scanned paper represent
chaotic and error-prone methods of exchange.
When moving to an eTMF application, both quality and efficiency can potentially be improved by
using system workflows to orchestrate document
authoring, collaboration, and collection processes.
Spending the time upfront to specify the appropriate access and roles for trial members within each
study, allows the eTMF to function as a hub for distributing and collecting documents. Structuring the
document exchange within the application removes
the cost of shipping paper and the complexity of
emailing individual files.
When designing an eTMF, the following three areas
help lay the foundation for success:
•Alignment around the TMF Reference Model: The
adoption of any application will be more successful if everyone using the system shares common
terminology.4 The DIA TMF Reference Model taxonomy outlines the clear definition and organization of TMF content using standard nomenclature. This common vocabulary allows people from
different organizations to communicate freely
and without the burden of translation. The zones,
classifications, and metadata form a shared language that all participants—CROs, sponsors, and
sites—can use to work with one another. “With
the DIA TMF Reference Model, companies adopt
a standardized approach with granular specifications down to the document metadata for all
studies globally. Standardizing reduces error that
comes with variation and the additional training
needed for internal and CRO staff when using custom taxonomies,” said Tamika Jackson, president
of the consultancy Corementum.
•Direct eTMF access for all study stakeholders:
Cloud-based eTMF systems provide a secure
and globally accessible location for all clinical
partners (sponsors, CROs, sites, regulators, and
ethical committees) to access, contribute, and
collaborate on trial content. Without direct access through the cloud, organizations are forced
to manually reconcile documents from contributing parties—a process that introduces delay
and human error. By having one single source
of truth, sponsors gain reliable visibility into the
trial process and improved inspection readiness.
“We were looking to move from our hybrid system
to a single, digital solution for TMF management
to improve quality, efficiency, and control while
allowing our colleagues and clients to access our
data through the cloud,” said Linda Danielson,
chief operating officer for IDDI, a global CRO that
recently transitioned to an eTMF solution.
•Visibility and performance with reporting and Next, understand how your TMF is being mandashboards: In addition to providing easier ac- aged throughout the trial:
cess and greater visibility, eTMF systems in- •Do you have SOPs to manage your TMF from
creation to inspection?
crease the control sponsors have over many
aspects of trial operations. Real-time status •How does each functional area file its documents? How does the process differ when docureports highlight gaps and issues as they occur,
ments are paper versus electronic?
improving organizations’ ability to get issues resolved, and decreasing the amount of effort and •Do you file documents as you go to maintain an
inspection-ready TMF or do you put it off until
time required for inspection preparations. Qualthe end?
ity metrics generated from the eTMF can help
organizations prepare for audits and inspections,
and contribute to a broader risk-based monitor- Finally, map out the transition:
•Which studies will be the first to leverage eTMF?
ing (RBM) strategy.
•How will active and archived studies be addressed?
Advanced Clinical, a global clinical outsourcing
organization, recently transitioned to a cloud- •What role will the central records team play in
managing the eTMF?
based eTMF for use of all of its customers worldwide. Julie Ross, executive vice president at Ad- •What SOPs need to change to reflect process
changes when going electronic?
vanced Clinical, said, “We can speed document
collection from start-up through trial close, and •What is the difference, if any, between your
planned structure and the TMF Reference
our clients get the visibility they need throughModel?
out the entire study.”
•What training is needed and who will provide it?
Managing a smooth transition
Fully transitioning from paper to electronic gives Answers to the above questions will vary by organization; the value lies in the act of discussing
life sciences companies the opportunity to re-imagand coming to agreement around each answer.
ine the way they operate and then make changes to
Once armed with a comprehensive understandincrease efficiency and improve collaboration with
ing of both the current and desired state, orgaCRO partners, affiliates, and investigator sites. In a
nizations are ready to begin transforming their
white paper published by eTMF consultancy Phlexprocesses while piloting an eTMF. Consultants
global, researchers note, “The transition from paper
at McKinsey suggest that companies shift to
to electronic trial master files promises improveelectronic slowly, applying it to just one or two
ments in capability, capacity, and quality.”8 However,
studies initially rather than all studies simulmaking this transition requires diligence. To suctaneously.9
If the eTMF is incorporated into
cessfully manage the change from a paper-based
daily operations, its dashboards and reports will
TMF to an eTMF, it’s crucial to first thoroughly
enable organizations to monitor study status
assess the current state of the organization. These
in real-time. At study close, organizations can
questions can help guide the transition:
compare the operational results of the pilot to
historic performance to see the value of their
First, understand your current state and partner
investment and plan for future trials.
•How are you currently maintaining your TMF?
Evolving your processes
Through your CRO or on-site?
Implementing an eTMF application creates an
•How do you gain or share visibility into the TMF
opportunity to automate and improve processes
with your partners?
•When you receive a TMF back from your CRO at rather than just streamline outdated paper processes. If electronic documents still get printed,
the end of the study, how is it transmitted?
•Does it provide sufficient long-term access or fa- signed, scanned, and manually tracked, the eTMF
can be adding steps to the process rather than recilitate content re-use?
moving them. “System efficacy is directly impacted
by the strength of an organization’s underlying
processes,” said Jackson. “In truth, it is as much
about how you re-engineer your processes as it is
about upgrading your technology. In order to adopt
an eTMF successfully, managers must align people
and process to leverage the new capabilities.”
When transitioning to an eTMF, some of the first
things to change are the roles and responsibilities
for filing documents. Historically, organizations
used a central records management function, but
as documents are born electronic, they should be
placed directly in the eTMF as part of the normal
course of work rather than as a separate step. This
can introduce a notable change in employee roles/
responsibilities. Companies must document and
clearly communicate who is responsible for placing every type of document in the eTMF, otherwise they’ll find an incomplete record since few
individuals consider it to be their responsibility
and most assume someone else is filing the documents. Additional emphasis must be placed on
clearly defining the roles of study partners. Partner on-boarding and training programs should be
developed to establish clear expectations around
process. And a tech support mechanism should
be established to address partners’ questions
about the software.
Configuring roles and responsibilities within
the eTMF application is part of building a repeatable framework that helps enforce and standardize
the process changes to come. And, in building a
repeatable framework, organizations are also defining the content types, workflows, and expected
timeframes for completing a given action.
The process changes that are built into system
workflows must also be reflected in the SOPs. This
provides a good opportunity to examine current
bottlenecks and identify where the eTMF—potentially with cloud access for partner—can eliminate
or automate steps in your process. Table 1 lists the
typical SOPs that should be updated when moving
to an eTMF.
Evolving your organization
For many organizations, the transition from paper to an eTMF is an evolution that spans regions,
functions, and skill sets, driving enormous efficiencies and cost savings throughout the organization.
To succeed, the process redesign effort must include the following elements:
•Developing a comprehensive understanding of
the processes already in place.
•Establishing a clear and attainable vision for the
•Training staff on the specific requirements and
changes for their role.
•Defining the methods and metrics for monitoring and managing change.
Each step creates clarity and helps keep the organization on track. According to Jackson, “Transitioning to fully electronic systems and processes allows
us to change the way we think about running clinical
trials. Rather than trying to modify what’s already in
place and largely maintaining business as usual, eTMFs help companies let go of the paper mindset altogther. You cannot conduct ‘business as usual’ when
you are making an intrinsic operational change.”
Kythera Biopharmaceuticals had been using a
homegrown hybrid paper/fileshare system that was
exceedingly difficult to access by important trial
partners such as its CROs, investigators, and other
internal staff across clinical and regulatory functions; it was also fraught with too many opportunities for error. The company, which was preparing
for rapid growth, decided to transition to an eTMF
and selected a cloud-based solution built specifically for the global life sciences industry. Recognizing the challenges in store while making this conversion, Kythera decided to change processes and
overhaul many of its SOPs to fully leverage the new
system’s capabilities. Although learning the taxonomy took a little time and integrating electronicdriven processes into Kythera’s daily workflows
required some upfront work, the company hoped
it would also help all involved re-envision the process and embrace the new system.
“We have had to adjust the way we think—from
a paper mindset to electronic. As an organization, Kythera cannot just adopt a sophisticated
electronic system yet maintain old paper processes. … We knew it was critical to re-engineer
our workflows, our processes, our team,” said Renee Fate, senior manager, document management,
for Kythera. “The biggest issue when it comes to
transitioning to a new type of system is the fear of
losing control. But when employees and partners
see the increase in efficiency that comes from a
more streamlined, repeatable process, then they
are more likely to adopt the system and accept a
new ‘digital’ business environment.”
Although the adoption rate of electronic trial
master file systems is rising,6 the promised efficiencies are just starting to be fully realized. Life
sciences companies that recognize that implementing an eTMF is not as simple as installing a new
technology but really a fundamental change in the
way they do business will get the most from their
new system for years to come.
As the 2013 “State of the TMF” survey suggests,
the No. 1 measure of eTMF success is increased
productivity.7 By reimagining corresponding processes to leverage eTMF capabilities, an eTMF can
contribute to powerful cultural changes around
operational efficiency. With the increased transparency, trial teams take a higher degree of ownership
in ensuring the quality and timeliness of study
Most importantly, the eTMF delivers value to
organizations that paper simply cannot—a TMF
that is inspection-ready at all times, a focal point
for sponsor-CRO collaboration, and visibility into
operational performance that spans the clinical organization and its partners.
Jennifer Goldsmith is vice president of Vault at Veeva
Systems, email: [email protected]
1. Drug Information Association (DIA), State of Trial
Master Files (TMF) Survey Results, by NextDocs Corporation. Jan 2014. More details available [http:// / Stateof TMF_ DIARegistrationPage.html]
2. Cutting Edge Information, Clinical Development and
Trial Operations (PH192), by Cutting Edge Information. November 2013. More details available
3. McKinsey & Company, Trial Master File Management:
Emerging Trends and Best Practices, by Jerel Davis, Edd
Flemming, Gary Mao, Lawrence Wal and Rachel
Zhang. 2012. More details available []
4. Gens and Associates, Managing Regulatory Information as a Corporate Asset Industry, Health Authority, and
Vendor Trends, by Steve Gens and Greg Brolund. Fall
2013. More details available []
5. Drug Information Association (DIA), State of Trial
Master Files (TMF) Survey Results, by NextDocs Corporation. Jan 2014. More details available [http:// / Stateof TMF_ DIARegistrationPage.html]
6. Drug Information Association (DIA), DIA TMF Reference Model 2012: Results of 2012 TMF Survey #2, by
DIA Document and Records Management SIAC.
November 2012.
7. Drug Information Association (DIA), State of Trial
Master Files (TMF) Survey Results, by NextDocs Corporation. Jan 2014. More details available [http:// / Stateof TMF_ DIARegistrationPage.html]
8. Phlexglobal LTD., Transforming Costly Paper Processes
into Value Driven Compliance, By Karen Redding. 2013.
More details available [http://www.phlexglobal.
9. McKinsey & Company, Trial Master File Management:
Emerging Trends and Best Practices, by Jerel Davis, Edd
Flemming, Gary Mao, Lawrence Wal and Rachel
Zhang. 2012. More details available []
10. Veeva Systems, The Paperless TMF: An Industry Benchmark. Survey conducted by Fierce Biotech, concluding March 2014.
Posted with permission from the July 7, 2014 issue of Applied Clinical Trials ®
Copyright 2014, Advanstar Communications, Inc. All rights reserved.
For more information on the use of this content, contact Wright’s Media at 877-652-5295.
Working in an Electronic World – How to Make a Smooth Transition to an eTMF
TMF Setup: Study, Country And Site Master
File Creation
Describes all the essential documentation
that needs to be filed in the TMF, including the
structure and indexing. If there is more than
one therapy area, there will either be a TMF
setup document for each area, or the TMF
setup document will be more general and list
the minimum and potential documents. It will
also contain a matrix listing the tasks, owners
and responsibilities, including ownership of
the official TMF.
If the eTMF supports the TMF Reference Model,
users can leverage it to create one or multiple
TMF templates. As part of the setup, user types
and roles can be incorporated by document or
document type, defining who can submit, review
and approve the document.
TMF Maintenance and Storage
Describes the submission, review, acceptance,
filing and reconciliation process for TMF
documents. A section for each functional area
(e.g. Clinical Trials Materials Management,
Biostatistcs, Data Management, Drug
Supply, Clinical Operations, Medical Monitor/
Clinical Science) can be included, or each
functional area will have its own separate TMF
management SOP. See Departmental TMF SOP.
When a user submits a document, modern eTMF
applications will automatically file it into the
TMF according to the document metadata. Once
it has been submitted, it will follow a workflow
defined in the setup process.
Site Closeout and Archiving of Site TMF
Describes how the study TMF will be
reconciled for site documents and the site
TMF archived. This should align with the
agreement between the sponsor and the
investigator on archiving of site documents
after the study is completed.
If sites have access to the eTMF application,
they can submit documents directly into the
sponsor TMF. Once a document has been
submitted, it will be routed through the review
and approval process defined during setup.
Study Closeout and Archiving of Study TMF
Describes how the TMF completion is verified
and then archived, including location of the
archive, and accessibility or retrieval of the
TMF documents by sponsor, sites and other
parties. Process for transfer of obligations
can also be added if there is a change
in ownership of the TMF once the TMF is
complete and archived.
Today, eTMFs are available that provide
advanced reporting and dashboard capabilities,
enabling sponsors to track missing documents
and documents that are still in the QC process,
identify which sites have submitted all their
documents, and most importantly, monitor
Document Quality Control SOP
Describes the quality control (QC) process for
the TMF documents. It will include a list of
the items to be verified for each document or
document type.
Documents can automatically be routed
through the QC, review and approval process,
automating a part of the QC process. Sponsors
can then report on how many documents are
being quality-checked, average length of the QC
process, and other processes, in the eTMF to
track performance and progress.
Clinical Records Room Management
If there is a separate Clinical Records team,
there will be an additional clinical records
room management SOP describing the process
for sending, filing, viewing and checking in or
checking out documentation in the records file
Clinical records management employees can be
set up with access to approved TMF documents,
so the content can be filed into the records file
User Role Management
Describes the process for which users are
given access and the type of access to the
TMF. Provision or removal of access will be
based on type of event (e.g. employee leaving
the company, new employee or employee is
changing roles), user role, and type of user.
This is a 21 CFR part 11 requirement.
eTMF applications that support SAML 2.0 for
SSO enable organizations to centralize user
management. These eTMFs allow trial managers
to create rules defined by user type, role, and
event (such as adding or removing a new user,
for example) to automate the level of access
different users receive.
Departmental TMF SOP
Describes the submission, review, acceptance,
filing, and reconciliation process for TMF
documents. The department is responsible
for ensuring the documents are filed
When a departmental user submits a document,
eTMF applications may automatically file it into
the TMF according to the document metadata.
Once it has been submitted, it will follow a
workflow defined in the setup process.
Inspection Readiness
Describes how to prepare and execute a
regulatory agency inspection, including how
the TMF would be made available. This
document is usually authored by a CQA and
includes who would be notified, assembly of
SME (Subject matter experts - first and second
chairs), set up of inspection, expectations of
personnel participating in the inspection, how
documents will be gathered and presented
to the SME, and how the information will be
provided in the inspection room. The events
would be broken down by what occurs before,
during and after an inspection (daily, weekly).
With eTMF applications, sponsors can
have greater oversight and assurance of
‘inspectability.’ These applications also help
inspections when they provide a specific role
within the system for health authority inspectors
to view approved TMF documents onsite or
eTMF System Description And Usage
If an eTMF is being used, this document
will provide a high level description of the
system and how it will be used. It will be
complemented with a working Instruction
document that provides further detail on the
system including design, validation package,
etc. It will also include in the appendix a
section on user role management describing
access to the eTMF based on each role and
user type.
Monitoring SOP
Describes the monitoring responsibilities and
activities associated with an eTMF.
Monitors can be given access to an online eTMF
to review TMF documents centrally or remotely,
eliminating most travel from the monitoring
CRO Oversight And Management
Describes how the sponsor will provide
oversight on the activities that have been
delegated to the CRO (via the task matrix) e.g.
weekly checks of the documents in the TMF by
the sponsor, monthly calls with CRO, etc.
Oversight SOPs can specify the desired level
of access to eTMF documents produced and
managed by CROs. TMF status and readiness
metrics can be specified and produced by the
eTMF application.
Policy On Correspondence And Emails
Defines which communication and how it
should be captured and filed into the TMF.
Forms of communication include emails, intraoffice messaging, letters, forms, telephone
calls, faxes, etc.
eTMF applications provide collaboration
features such as annotations, task assignment,
notifications and messages to users, and
are automatically stored in the system.
Communications are automatically stored in
the system. SOPs may be updated to reduce
the usage of communication channels that lack
tracking and reporting capabilities.
By: Jennifer Goldsmith
Table 1. SOP Changes When Adopting an eTMF Application