Learn about the Trial Master File, eTMF and how efficiencies can be during the clinical trial process.

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 •Registration in •Form FDA 1572
•CRF suitability, items concerning Clinicaltrials.gov •Financial Disclosure
overall 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
Sponso
IRB
Trial r
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)

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

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.