TMF Reference Model Training Part 2

Summary

The video script introduces the TMF Reference Model, a global initiative to standardize the content, structure, and naming conventions of clinical trial master files. It outlines the model's fourfold purpose: standard content, naming, structure, and metadata. The script explains how the model, developed by a volunteer team, helps in organizing documents into 11 zones and sections for easy retrieval and compliance. It also discusses the change control process and the benefits of implementing the model, such as standardization, simplified CRO engagement, and ease of merging multiple TMFs.

Takeaways

• 📚 The Trial Master File (TMF) is a collection of essential documents that must be maintained by sponsors and investigators for every clinical trial, as outlined by ICH GCP and EU Regulation 536/2014.
• 📈 The TMF Reference Model is a global initiative that standardizes the content, naming, structure, and metadata of the TMF to facilitate evaluation, compliance, and regulatory inspections.
• 🌐 The model is developed and maintained by a volunteer steering committee, with a change control process to ensure ongoing relevance and accuracy.
• 📂 The TMF is organized into 11 zones categorized by functional areas, such as Trial Management, Regulatory, Ethics Committee/IRB, Site Management, Safety Reporting, and more.
• 🔍 Each zone contains sections and artifacts, which are further divided into sub-artifacts for detailed document classification and easy retrieval.
• 📝 Standard naming conventions help avoid inconsistencies in document references, both within and between organizations.
• 📊 The structure of the TMF supports both paper and electronic systems, aiding in consistent filing and rapid retrieval of documents, especially during audits or inspections.
• 🔗 The TMF Reference Model provides a common starting point for companies, streamlining the process of preparing and maintaining TMFs in compliance with regulatory requirements.
• 🤝 Implementation of the TMF Reference Model simplifies interactions with CROs, as both parties can follow a similar structure, making collaboration more efficient.
• 🔄 The model allows for the consolidation of multiple TMFs into a single structure, useful for managing documents throughout a study's lifecycle.
• 💡 The TMF Reference Model is a tool for standardization, consistency, and efficiency in clinical trial documentation, benefiting both sponsors and regulatory bodies.

Q & A

What is the primary purpose of the Trial Master File (TMF) according to the ICH E6 EU Regulation 536/2014?

The primary purpose of the TMF is to contain the essential documents that allow for the evaluation of the trial's conduct and the quality of the data generated. It must be readily available and directly accessible upon request to the member states.

What are the two key requirements for the Sponsor and Investigator regarding the TMF?

The two key requirements are that the Sponsor and Investigator must keep a TMF at all times for the clinical trial they are conducting, and the TMF must be readily available and directly accessible upon request.

According to the ICH GCP, what are considered Essential Documents?

Essential Documents are those documents that, individually and collectively, permit the evaluation of the conduct of a trial and the quality of the data produced. They demonstrate compliance with Good Clinical Practice standards and applicable regulatory requirements.

What does the TMF Reference Model aim to standardize?

The TMF Reference Model aims to standardize content, naming, structure, and metadata to facilitate consistency across the industry and ease the process of document retrieval, especially during audits or inspections.

How does the TMF Reference Model support both paper and electronic systems?

The TMF Reference Model provides a standard structure that can be applied to both paper and electronic systems, or a hybrid of both, to ensure consistent filing and rapid retrieval of documents.

What are the 11 zones that make up the TMF Reference Model?

The 11 zones include Trial Management, ClinOps Central Trial Documents, Regulatory, Ethics Committee and IRB, Site Management, Trial Supplies, Safety Reporting, Central Local Testing, Third Parties, Data Management, and Statistics.

How does the TMF Reference Model help in organizing documents for a paper TMF?

The TMF Reference Model organizes documents through trial-level files, country-level files, and site-level files, allowing for easy retrieval during inspections and aids in the completeness review of documents.

Who controls the versions of the TMF Reference Model?

A Change Control Board, with a structure that includes a chair and deputy chair, and members responsible for reviewing and categorizing change requests, controls the versions of the TMF Reference Model.

What are the different types of releases for the TMF Reference Model?

The different types of releases include Maintenance Releases (e.g., 3.0.1 for minor changes), Minor Releases (e.g., 3.1 for substantial changes without compatibility issues), and Major Releases (significant changes that may have compatibility issues).

What are some benefits of implementing the TMF Reference Model?

Benefits include standardization of content and structure, limitation of customization, simplified engagement with CROs, and ease of consolidating multiple TMFs into a single structure.

How can one engage with the TMF Reference Model community for further discussion and networking?

Individuals can join the discussion group at tmfreferencemodel.com/register to engage with the community, showcase knowledge, network, and participate in discussions.

Outlines

00:00

📚 Introduction to TMF Reference Model

This paragraph introduces the speakers, Chole Xi Van from LMK Clinical Research Consulting and Donna Dorzinski from Just in Time GCP, both members of the TMF Reference Model Steering Committee. They begin by defining the Trial Master File (TMF) as per the EU Regulation 536/2014, emphasizing the necessity for sponsors and investigators to maintain it for all clinical trials. The TMF should contain essential documents that verify the conduct of the clinical trial and the quality of data generated, and should be readily available and directly accessible upon request. The essential documents are further explained as those that permit evaluation of the trial's conduct and the data's quality, demonstrating compliance with Good Clinical Practice (GCP) and regulatory standards.

05:01

📈 TMF Reference Model: Purpose and Structure

In this section, the speakers delve into the purpose of the TMF Reference Model, which is to standardize content, naming, structure, and metadata. The model is based on a global consensus, expanding upon the minimum list of documents outlined by ICH GCP Chapter 8. It aims to avoid scope creep and provide a consistent interpretation of what should be included in a TMF. The paragraph also introduces the structure of the model, detailing the 11 zones organized by functional areas such as trial management, regulatory, ethics committee, site management, safety reporting, third parties, and data management. Each zone contains sections and relevant content for specific activities, providing a systematic way to file and retrieve documents.

10:01

📃 Application of TMF Reference Model to Paper TMF

The final paragraph discusses the practical application of the TMF Reference Model to a paper-based TMF. It explains the organization of trial-level files, country-level files, and site-level files to facilitate easy retrieval during inspections or audits. The paragraph also covers how to use an Excel filter to identify relevant artifacts for specific content. The control and maintenance of the reference model version are discussed, including the change control board, procedures, and responsibilities. The benefits of implementing the TMF Reference Model are highlighted, such as standardization of content and structure, simplification of CRO engagement, and ease of consolidating multiple TMFs. The speakers conclude by inviting participants to join their discussion group and the TMF Reference Model project team.

Keywords

💡Trial Master File (TMF)

The Trial Master File (TMF) is a collection of essential documents that are required to be maintained by the sponsor and investigator for a clinical trial. It serves as a record of the trial's conduct and the quality of the data generated. As per the EU Regulation 536/2014, the TMF must be readily available and directly accessible upon request to the member states. The TMF is crucial for verifying the compliance of the trial with good clinical practice standards and regulatory requirements.

💡ICH GCP

The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) guidelines provide a unified standard for the design, conduct, recording, and reporting of clinical trials. These guidelines are critical for ensuring the protection of trial subjects and the quality of trial data. In the context of the video, ICH GCP defines what constitutes essential documents within the TMF and outlines the standards for clinical trial management.

💡Reference Model

The Reference Model discussed in the video serves as a standardized framework for the content, structure, and organization of the Trial Master File. It is developed by a global team of volunteers and is based on ICH GCP guidelines and industry feedback. The model aims to provide a consistent approach to TMF management, facilitating compliance, ease of use, and efficient retrieval of documents during audits or inspections.

💡Standard Content

Standard Content refers to the agreed-upon set of documents and records that should be included in the Trial Master File as per the TMF Reference Model. This standardization helps ensure that all necessary information is consistently captured and maintained across different trials and organizations, making it easier for regulatory authorities to evaluate trials and for organizations to demonstrate compliance.

💡Standard Naming

Standard Naming is a convention used within the TMF Reference Model to consistently label and refer to documents and artifacts. This standardization helps avoid confusion and ensures that the same terminology is used within an organization and across different organizations, facilitating clear communication and efficient document management.

💡Standard Structure

Standard Structure refers to the organized layout of the Trial Master File, which is designed to support both paper and electronic systems. This structure facilitates consistent filing practices and rapid retrieval of documents, which is particularly important during audits or inspections. It also aids in distributing responsibilities for maintaining different sections of the TMF across various stakeholders.

💡Standard Metadata

Standard Metadata are consistent data elements that describe the characteristics of documents and artifacts within the Trial Master File. These metadata encourage the adoption of good practices for document retrieval and promote consistency across the industry for the exchange of content, which is crucial during audits or inspections.

💡Change Control Board

The Change Control Board is a group responsible for managing updates and changes to the TMF Reference Model. This board reviews, categorizes, and triages change requests, ensuring that the model remains current and relevant while maintaining compatibility with existing configurations. The board's role is critical for the ongoing development and maintenance of the Reference Model.

💡Version Control

Version Control refers to the management of different iterations of the TMF Reference Model. It involves tracking changes, categorizing them, and releasing new versions to reflect updates and improvements. This process ensures that the model remains relevant and useful for organizations while maintaining compatibility with existing systems and configurations.

💡Artifacts

In the context of the TMF Reference Model, Artifacts refer to any digitized content or documents that are part of the Trial Master File. These can range from data files and documents to multimedia content. Artifacts are categorized and filed within the model's structure, allowing for efficient organization and retrieval of relevant information.

💡Zones and Sections

Zones and Sections are part of the hierarchical structure used in the TMF Reference Model to organize documents and artifacts. Zones are broad functional areas, such as Trial Management or Regulatory, while sections within each zone contain more specific categories of content related to particular activities. This structure aids in the classification, search, and retrieval of documents.

Highlights

Introduction of the TMF Reference Model and its steering committee members.

Definition of the Trial Master File (TMF) as per ICH E6 and EU Regulation 536/2014.

Essential documents are those that permit evaluation of a trial's conduct and data quality.

The TMF Reference Model is based on a minimum list of essential documents from ICH GCP Chapter 8.

The TMF Reference Model includes additional child-related records for a comprehensive evaluation of the trial.

The purpose of the TMF Reference Model is to standardize content, naming, structure, and metadata.

The TMF Reference Model is developed by volunteers globally, providing a wide range of perspectives.

Standard naming in the TMF Reference Model avoids inconsistencies in terminology within and between organizations.

Standard structure supports both paper and electronic systems for consistent filing and rapid retrieval.

Standard metadata encourages good practices for document retrieval and industry consistency.

The TMF Reference Model is organized into 11 zones categorized by functional areas.

Each zone in the model contains sections and relevant content for specific activities.

Artifacts in the TMF Reference Model can be documents, data files, or any digitized content.

The TMF Reference Model provides definitions for artifacts to guide document filing.

Sub-artifacts offer a layer of filing for more detailed document organization.

Application of the TMF Reference Model to paper TMF involves organizing documents at trial, country, and site levels.

Change control procedures and a board ensure the maintenance and updates of the TMF Reference Model.

Benefits of implementing the TMF Reference Model include standardization, simplification of CRO engagement, and ease of merging multiple TMFs.

Transcripts

hi everyone this is chole xi van from

lmk clinical research consulting

i am a member of the tmf reference model

steering committee and so excited to be

here with you today

hi i'm donna dorzinski from just in time

gcp also a member of the tmf reference

model steering committee and we are

going to be presenting to you today part

two of the tmf

thank you so much for joining part two

of today's training

let's get started

with the tmf reference model defining

the model

so let's start with a couple of

definitions

what is the trial master file for the

tms

eu regulation 536 2014 tells us that the

sponsor and the investigator shall keep

a clinical trial master file or tml

the clinical trial master file shall at

all times contain the essential

documents relating to that clinical

trial for which verification of the

conduct of a clinical trial and the

quality of the data generated

it shall be readily available and

directly accessible upon request

to the member states so just a couple of

things to point out here

number one that the sponsor and the

investigator

must keep a tmf at all times for the

clinical trial in which they are

conducting

number two

the clinical trial shall be readily

available and number three directly

accessible upon request so just a couple

of things to highlight from this

definition

what are essential documents so ich gpp

tells us in section 8 that essential

documents are those documents that

individually and collectively permit

evaluation of the conduct of a trial and

the quality of the data produced

these documents serve to demonstrate the

compliance of the investigator

the sponsor

and monitor with the spot the standards

of good clinical practice and with all

applicable regulatory requirements

so let's define the tms preference model

so we start with that minimum list of

essential documents as defined by ich

gcp chapter 8.

then we kind of expand that to include

other child-related

records

that permit the evaluation of the

contest of the trial and the quality of

the data produced that

definition may sound familiar because

that's directly from ich

these two

combined make up the trial master file

for the tms

then we have some outline outlier

documents

or supporting files such as computer

sdlc files gmp manufacturing files and

vendor selection files these are

typically considered outside the scope

of the tms you may also have other

business records that fall outside of

that

the scope of the tms as well

so what is the purpose of the trial

master file preference model the tms

reference model so it's really four fold

number one standard content

number two standard naming number three

standard structure and finally standard

metadata so let's take a closer look at

each one of these

number one the standard content so this

is really the industry's opinion on what

is kept in the tmf

so as you may have heard in part one the

tmf reference model is made up of

volunteers from all around the world so

it's really great to get their insight

on what should be in the tmf reference

model

the team of reference model really

expands upon the minimum list

of documents that are that's found in

e6 release 2.

it's a consistent interpretation based

on pure opinion and regulatory feedback

and it avoids scope creeps for the trial

master file have you ever thought i

wonder if this document belongs in the

tmf well the tmf reference model answers

that question for you

the next purpose of the tmax reference

model is standard naming and this is

based on ich c6 release 2 section 8 and

industry accepted terminology

this avoids one artifact or document on

being referred to

using different terms within an

organization or between organizations

it

has the potential for avoiding company

specific terms we want to call the same

artifact the same thing

next is standard structure

this is to support paper and electronic

systems or a hybrid if you're using both

this facility consistent filing and

rapid retrieval which is very important

especially during an audit or an

inspection

and it's helpful when responsibility for

maintaining different sections

of the tmf is distributed across several

stakeholders so for example the sponsor

the bureau or consultant

the next purpose is standard metadata

this encourages adoption of good

practices to facilitate that document

retrieval which again is very important

especially during an audit or an

inspection and it encourages consistency

across the industry for exchange of

content

now i will turn it over to to don

zorzinski for the structure and content

of the model thanks chile

i'm going to talk a little bit about the

actual reference model itself

and the 11 zones that make up the

reference model so as you can see

they're kind of organized by functional

area right so trial management is

clearly clinops central trial documents

represent things like medical writing

icfs protocols but also clinical

operations documents as well

we have our regulatory section we have

our ethics committee and irb which is

again back with clinical operations

we have site management i plea trial

supplies that can be either clinical

trial materials or clinical apps as well

because of the site documents

safety reporting that's pretty clear

central local testing those are your

like your laboratories or your

other testing groups third parties

that's really where we put all of our

third-party documentation and then data

management and statistics is pretty

self-explanatory

so within each of the zones there are

sections and then within each section

there's um

content that's relevant to a specific

activity so for example third-party

setup it's all of the different

artifacts or document types that are

related to that particular section

you'll notice that we you see a general

section here within each of the zones

there are general is a general section

and in each general section there are

relevant communications

tracking information meeting materials

and file notes and so that provides a

section where you can file those types

of documents at the zone level

sections are helpful in terms of

classifying content and also searching

for artifacts

so artifacts can be things like data

files documents maybe a video some type

of a media

any kind of digitized content those are

all considered artifacts it could be one

document or it could be lots of

different documents for example inform

consents is an artifact which you could

have different types of informed

consents filed in that section and it

also includes associated records so when

we have documentation like translations

or qc checklists baby document approvals

all of that content can be filed with

those artifacts as well

i love this particular section because i

really think it helps us

figure out where to file things

all of the artifacts have definitions

and the definitions provide us the

thinking between the different types of

documents that might be filed in that

particular section

so for example uh

for a note to file it explains that the

nota file is to document any decision or

clarification related to information in

that zone and so it actually gives you

an explanation you can see in data

management plan it also provides for you

some examples so maybe the data quality

plan goes there the crf design document

so it helps you when you're searching

for where to file a document it provides

you some additional information to guide

your selection

we've also included the ich code and

this is really the justification

within ich for that particular content

so you'll see not every single document

actually has an ich link but the

majority of them do and so that's the

source for explaining why that

particular document type is required

and then we have our sub artifacts and

our sub-artifacts really provide a next

layer of filing so within an artifact we

might have multiple sub-artifacts so for

example your risk management plan you

could put your plan there you could put

your risk assessment document and you

could put your risk log it allows you to

file documents at a lower level of

granularity right so we don't just put

it in risk management plan

but we have that sub artifact which

gives you a little bit more detail

so how does all of this work with the

paper tmf

when you're taking the reference model

and applying it to the paper tmf we have

travel trial level files we have country

level files per country and then we have

site level files so we organize all the

trial documents together and then each

country has its own documents so for

example the us would have all of the

documents related to the us file there

so all of the different

zones and

sections and artifacts would be filed

within that country and then we carry it

one level lower to the site right so

each site has its own collection of

documents and that really helps you file

your paper records in a way that's

easily retrievable during an inspection

but also as you might be doing your

completeness review or if you're simply

just looking for documents

so how do we actually apply it when we

create a paper tmf and so what we do is

we want to be able to filter

in that excel so you actually take your

excel and you filter for all the trial

content

and then that tells you what

particular artifacts are relevant for

that content so here we have an example

where we've filtered for country level

and we've identified all of the country

specific documents

so who controls the versions of the

reference model so there's a change

control board

um and this is the structure as of march

2021 there are 15 members with kelly

robinson as the uh chair and joy and

malia as the deputy chair the

deliverables are that they meet twice a

month they have a change control

procedure there's a racy that identifies

who's responsible for what and then of

course there's a change control tracker

their job is to review and categorize

all of the different change requests and

then they triage these change requests

to the different to the different zone

teams

and then the zone teams actually make

their recommendation

from there the change control board

actually delivers the new versions of

the reference model

so just to kind of explain the version

definition the maintenance release would

be like version 3.0.1 and that's like

maybe a minor change right so like a

maybe addition of a sub artifact a

clarification

then we have a minor release which is

just 3.1 that's where we have a

substantial change in content but

there's no compatibility issues um

really maybe addition of optional column

when we added milestones a major release

is where we are likely to have some

compatibility issues and it's a pretty

significant change you don't actually

you don't actually need to be working on

the latest version

what's important is that you understand

your configuration and your

configuration works for your

organization

so what are some of the benefits that we

gain by implementing well first of all

it standardizes your company content and

structure and it limits customization

right so we don't want to customize it

substantially we want to basically

follow the regulatory requirements and

by aligning with the reference model we

know that it's going to be and for an

inspector it will be consistent across

companies oftentimes company specific

requirements are driven by legacy or

tradition or personal opinion the

reference model kind of removes all of

that and kind of creates a starting

point

it also simplifies the engagement of

cros so that if your cro is using the

reference model and you are using the

reference model the configuration should

be very similar

and then lastly it helps you when you

want to bring multiple tmfs into a

single tmf structure whether you do it

in real time or at different intervals

over the life of the study

thank you so much for joining us today

if you have any questions about the

material that chile or i presented we

ask you to join our discussion group at

tmf reference model dot com slash

register it's a great opportunity to

show your knowledge to network and to

just have too much fun

and if you would like to join the tmf

reference model project team but be

prepared to work

feel free to

click on the link tmf

refmodel.com

or excuse me slash groups slash i o

g main the link below thank you so much