This document discusses the benefits of moving from a traditional paper Trial Master File (TMF) to an electronic TMF (eTMF). An eTMF allows documents to be stored centrally and accessed globally through a secure system, improving efficiency. It reduces costs from activities like document retrieval and duplication of work. An eTMF also enhances quality, compliance and transparency. The document argues that in order to keep up with increasing regulations and development timelines, companies need to adopt eTMFs to gain operational efficiencies and get in the "fast lane".

1. Move into the Fast Lane with eTMF

2. Questions we’ll answer:
 What is a TMF?
 What are eTMFs and their benefits?
 What is a DIA TMF Reference Model?
 How do IRBs/Sponsors/CROs/Sites benefit?
 How does moving to an Electronic TMF put my
company in the fast lane?

3. What is a TMF?
 Traditionally kept as a set of binders, the Trial Master File
(TMF) includes an array of document types ranging from Site
Contracts to Clinical Study Reports with numerous
documents of each type, often resulting in a total collection
of thousands of documents in each TMF.
 According to Good Clinical Practice (GCP), “These
documents serve to demonstrate the compliance of the
investigator, sponsor and monitor with the standards of Good
Clinical Practice and with all applicable regulatory
requirements.” – ICH GCP E6 (R1)

4. Essential Documentation Collected during
a Clinical Trial
Pre-site selection Site Selection Regulatory Site Set-up
•Investigators Brochure •Confidentiality agreement •Notification of IND # or •Protocol signature page
•Protocol •Pre-study visit (investigator CTA approval •PI & Sub-I cv
•Informed consent selection,site suitability, •Registration in •Form FDA 1572
•CRF items concerning overall Clinicaltrials.gov •Financial Disclosure
study conduct) •IRB/IEC Submission
Monitoring Investigational Product Safety Centralized Testing
•Trial initiation monitoring •Instructions for handling •Safety Management plan Facility
report •Accountability •SAE reports •Normal ranges
•Site training documentation Documentation •Pharmacovigilance •Certificate of accreditation
•Monitoring visit report Database Line Listing
•Protocol deviations
Third party Oversight Data Management Statistical Analysis Clinical Study Report
•Confidentiality Agreement •Data Mgmt. Plan •SAP
•Contractual Agreement •CRFs •Randomization Plan
•EDC •Datasets
•Programs

5. Essential Documents
 Documents which individually and collectively permit
evaluation of the conduct of a trial and quality of the data
produced.
 Usually the documents are audited by the sponsor’s
independent audit function and inspected by Health
Authorities as part of the process to confirm the validity of
the trial conduct and the integrity of the data collected.

6. Essential Documents per ICH GCP E6 (R1)

7. TMF Challenges
 The Life Science industry is facing pressure to cut costs while
facing increasingly challenging regulatory requirements-
which have increased the cost.
 With more clinical studies being conducted globally, paper
TMFs are becoming more of a challenge as file numbers
increase.
 A study by the multinational defense, security and aerospace firm
BAE Systems showed that 80 percent of employees waste an
average of 30 minutes per day retrieving information, while 60
percent are spending an hour or more duplicating the work of
others (Dukart, 2007; Martin, 2004).

8. What is an electronic TMF System?
 An eTMF system is the application of a 21 CFR part 11
compliant electronic document management system.
 Documents and content are stored centrally on a computer
server “cloud” eliminating the need for regulatory binders.
 The system is accessed via a secure internet connection
globally with auditable security.
 An eTMF automates time consuming error-prone paper-
based processes.

9. Features of an eTMF System
 TMF taxonomy – includes document names, descriptions,
categories
 TMF metadata –standards-based data about the documents
that become part of the TMF document record
 Allows customization of the eTMF taxonomy for addition of
new document types and metadata
 Notifications can be sent to key information to stakeholders
 An intelligent, precise search

10. What is the TMF Reference Model?
 In 2009, the Drug Information Association (DIA) embarked
upon an effort to define a standard clinical trial master file
taxonomy or “reference model” for use by industry.
 This collaborative effort involved more than 159
representatives from 105 biopharmaceutical companies,
CROs, consultancies, technical vendors, industry groups,
healthcare, academia, non-profit/NGO and regulatory
agencies (MHRA and FDA).

11. Goals of the TMF RM
 A primary goal of the TMF RM initiative is to provide a
single, unified interpretation of the regulations in the form of
a list of TMF document types/artifacts that would be
accepted by all clinical trial stakeholders and which can be
adopted or adapted by any company, CRO, institution or
other organization.
 The TMF RM is intended to provide a collaborative
advantage to stakeholders in creating and managing their
TMFs.

12. Organization of the TMF RM
 The TMF RM consists of standardized taxonomy and
metadata and outlines the clear definition and
organization of TMF content using consistent
nomenclature.

13. Zones

14. Metadata
 Alternate names, Definition/Purpose, Unique ID
Number, Study No/Trial No/Protocol No
 Used for metadata and to define paper TMF format:
 Trial Level Document, Country, Site No/ID
 Inherited Metadata from Trial No:
 Product/Compound, Indication, Trial Phase, Route of
Admin
 Artifact date as defined by convention, Map to Current
Sponsor Document Name, Location of Artifact

15. Example of DIA TMF Reference Model

16. From regulatory binders to
electronic file folders

17. Why resist change?
 Most resistance is due to stakeholders seeing no need for change.
They have a long history of working with paper-based data
collection that have what they consider to be “good results.”
 According to Neuer (2010), most companies cite the upfront cost
to be a major barrier to implementing a new electronic system. As
part of this perception, they may believe that solutions are too big
for smaller companies, or they may be unsure about the vendor’s
ability to deliver high-quality technology, training, and customer
service.
 There are many questions as to how the system will be
implemented and how processes, standard operating procedures,
and jobs will change to accommodate the new technology.

18. Stakeholders
Site
IRB Sponsor
Trial
Master
File
(TMF)
Health
Authorit CRO
y

19. Goals for Stakeholders
 Reduce time associated with file requests, audits, and
submissions
 Increase quality
 Easily locate all documents
 Enforce security and regulatory compliance
 Conserve resources (personnel, time, money)
 Save trees

20. Challenges for Stakeholders
 The document intensive nature of the business requires a great
deal of internal and external collaboration and management of
numerous documents in accordance with regulations.
 Time and money spent on the tracking, routing, review, approval
and archiving
 Difficulties finding documents
 Issues with audits/compliance/inspections
 Storage space, shipping, supplies
 Slow organizational responsiveness

21. Barriers to Collaborative Management
 Lack of a centralized globally accessible platform to manage
and store essential study documentation.
 Inconsistent document management processes across and
between organizations.
 Inconsistent or incomplete work assignments.
 Inefficient notification of key events.
 Incomplete, missing, expired or redundant documentation.

22. How will eTMF help?
 Provides operational efficiency, improves quality, and can
help companies reduce the internal costs of maintaining
electronic filing systems and reduce the administrative
expense of locating documents .
 By strategically integrating business process, people, and
technology, companies can make more effective business
decisions, exponentially increasing value.

23. Operational Efficiency
 When operational efficiency is improved:
 The same total number of employees can do a greater amount
of work
 Employees can be re‐assigned to new/different roles that add
greater value
 Standardization and consistency of processes is improved
 The time to market will be shorted, thus increasing profit
margins and revenues
 Quality will be enhanced

24. Quality
 The quality of Regulatory documents is being compromised as
companies try to do more work with less people.
 One survey estimates that business-technology professionals in
the industry are spending up to 22 percent of their work week
on compliance (Smith, 2003).
 Standard Operating Procedures are estimated to cost a
Pharmaceutical organization $1-2 million a year (Semple,
2003; Whalley).

25. Quality cont.
 Research suggests that while costs associated with drug
development are increasing at an annual rate of 11.8 percent,
sales are only growing from 2% to 5% in the United States
(Neuer et al., 2010).
 All the while, staffing is not increasing.

26. Cost
 Focusing only on the upfront costs overlooks the significant
downstream cost savings being realized by being able to
reduce human error and time spent on quality assurance.
 These benefits tend to be cumulative as efficiencies linked to
new technologies generally increase over time as end users
gain familiarity with them through repeated use.
 Dramatic reduction in the need to print, distribute, and store
multiple copies at different sites

27. Benefits beyond time, cost and quality
 Management of Regulatory Changes: State, Federal and
industry regulations continue to grow and evolve.
 Risk Management: Significant risks and penalties for non-
compliance, including fines, and customer lawsuits.
 Access to the trial data that sponsors need quickly and
effectively
 Clients can better isolate trial inefficiencies and achieve
significantly higher quality and cost savings
 Centralized documentation
 Security (restricted access)
 Secure electronic backup
 Visible 24/7 over the internet

28. More benefits
 Investigator relationship management
 Investigator and site identification and recruitment
 Site management (monitoring actual enrollment relative to
planned, IRB approval and decision, etc.)
 Protocol and study documentation preparation
 Reporting
 Integration with other systems
 Consistent archive format

29. So why should I move to eTMF?
 Increased compliance
 Enhanced security
 Operational efficiency
 Increased transparency
 Simplified tracking
 Significant cost savings
 No new hardware
 Better document quality
 Easy and fast search and retrieval

30. Get out of the slow lane!
 By the year 2020, the life sciences market is expected to
reach $1.3 trillion, and larger companies may have over
100 active compounds in development, as well as
numerous compounds on the market (Sichort & Booth-
Genthe, 2010).
 According to the National Center on Education and the
Economy (NCEE), “taking a month off development
time can generate an additional $40 million in sales for
the average drug.”
 You need to make changes to get in the fast lane and keep up.

31. Wrap up
 Today we learned about TMFs, eTMFs, and how having an
eTMF can keep your company moving forward at a fast pace
and make you a front runner in the race. It’s time to move
into the fast lane with an eTMF.
 For more information contact Mission3 at
info@mission3.com or follow us on Twitter @adair_turner
or @dirkbeth.