navigating the new trial master file regulatory …

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NAVIGATING THE NEW TRIAL MASTER FILE REGULATORY LANDSCAPEPREPARING FOR 2018

JOIN THE CONVERSATION#TMFREGUPDATES@MONTRIUM


Christina MantziorosClinical Solutions Specialist

Montrium

Paul FentonCEO

Montrium

Presenters


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NAVIGATING THE NEW TMF REGULATORY LANDSCAPE:PREPARING FOR 2018

JOIN THE CONVERSATION#TMFREGUPDATES

Introduction

• Things are changing.....• Regulations are evolving

• Technology is evolving

• The role and scope of TMF is evolving




Disclaimer

The views and opinions expressed in this presentation are those of the authors and do not necessarily reflect the official policy or position of any regulatory agency.




The New Regulatory Landscape1What’s new in TMF?




Word Cloud




What We’re Referencing

FDA CGMP

Guideline on GCP compliance

in relation to trial master file

(paper and/or electronic) for

content, management, archiving,

audit and inspection of clinical

trials (March 2017)

Integrated addendum

to ICH E6(R1):

Guideline for Good

Clinical Practice E6(R2)

(November 2016)

MHRA GxP Data Integrity

Definitions and Guidance

for Industry Draft version

(July 2016)

FDA Data Integrity and

Compliance with CGMP

(April 2016)

FDA Use of Electronic Records and

Electronic Signatures in Clinical

Investigations Under 21 CFR Part

11 Questions & Answers’

(June 2017)

21 CFR PART 11MHRA GxP

Data Integrity Definitions

ICH E6 (R2)

EMA15975/2016




Key Highlights

Certified Copies & Destruction of Paper

Audit Trails

TMF Scope & Signposts

TMF Exchange

Timeliness

Direct Access

Record Retention

Cloud Computing

Site Documents/ISF

Risk-based TMF

Sponsor Oversight





“A copy (irrespective of the type of media used) of the original record that has been verified (i.e. by a

dated signature or by generation through a validated process) to have the same information, including

data that describe the context, content and structure, as the original.”

“[…] When a copy is used to replace an original document (e.g., source documents, CRF), the copy

should fulfill the requirements for certified copies.”

“The copy of the original record should be verified as having all of the same attributes and information

as the original record and certified as indicated by a date signature.”

“A certified copy is a paper or electronic copy of the original record that has been verified (e.g. by a dated

signature) or has been generated through a validated process to produce a copy having the exact

content and meaning of the original.”

ICH

EMA

ICH

FDA





Big Issues• FDA guidance is currently not in line with ICH E6 R2 or EMA

• How practical is it to sign certified copies (electronically or handwritten)?

• Do we destroy paper or not?

Practical considerations• Define what is a record and what you understand to be a certified copy

• Develop a process for validation of certified copies, including ongoing QC, should be detailed in SOPs to ensure

consistency

• Remember that a certified copy is only required if the copy is permanently replacing the original or if the eTMF is being

presented as the official TMF, for example, during an inspection

• Only destroy paper if you are confident that your validated process works

• Remember to initiate documents electronically if you can




Audit Trails

“audit trail […] to identify date/time/user details for creation, uploading, approval and deletion of and changes to a document”

“audit trail is a process that captures details of information, such as additions, deletions, or alterations, in an electronic record without obscuring the original record. An audit trail facilitates the reconstruction of the course of such details relating to the electronic record.”

"Electronic audit trails include those that track creation, modification, or deletion of data (such as processing

parameters and results) and those that track actions at the record or system level (such as attempts to access the

system or rename or delete a file)."

"There should be adequate traceability of any user defined parameters used within data processing activities. Audit

trails and retained records should allow reconstruction of all data processing activities regardless of whether the

output of that processing is subsequently reported or otherwise used."

EMA

FDA

MHRA

FDA




Big Issues• When does an artifact become a record?

• What metadata or processing parameters need to be audit trailed?

• What is an audit trail vs transaction log and where does it apply?

• Data integrity guidance is still in draft

Practical Considerations• Define what you consider to be a record (records management process) and what needs an audit trail

(system requirements) based on your interpretation of the regulations

• Transaction logs are useful – ask your vendors what they offer and include this in your specifications

• Lobby the regulators to come up with better descriptions and requirements

Audit Trails





"The sponsor and investigator/institution should maintain a record of the

location(s) of their respective essential documents including source documents.”

“The sponsor and the investigator should identify and make a record of the

location(s) of all the potential documentation that is considered to form the TMF,

even if several locations, departments, country organizations and systems are

involved, so that it is effectively organized.”

ICH

EMA




Big Issues• How do you present TMF information to an inspector that is contained in multiple

different systems and locations?

• What is TMF relevant?

• When multiple systems are involved, what is the authoritative source?

Practical Considerations• In the TMF plan, specify what is TMF relevant, authoritative source vs. shadow and where

this information is being held

• Label artifacts in eTMF as authoritative source or shadow copies

• Identify TMF records using signposts within your eTMF, if your system allows you to do it

• Define process for access to signposted content being held in different locations


TMF CONTENT




TMF Exchange

“When different TMF systems are linked to facilitate the trial conduct, for example the CRO eTMF system

uploads documents into the sponsor eTMF system, the process for transferring documents should be

robust and should be validated to prevent failure of transferring parts of the entire content of the

original TMF without loss i.e. there should be a demonstrable 1:1 mapping between the content of the

two systems.”

“During an inspection, FDA will focus on any source data that are transferred to another data format or

system to ensure that checks are in place and critical data are not altered in value or meaning during the

migration.”

EMA

FDA




Big Issues• How do you conduct exchange of TMF information across different eTMF systems:

• At the end of a study?

• In the case of a merger and acquisition?

• In the case of interim TMF transfers?

• In the case of an inspection?

• Mapping metadata and migrating content is time consuming and error prone

• Transferred content, if electronic, must be held in a compliant manner

Practical Considerations• TMF RM exchange mechanism standard will hopefully solve this problem

• Find out from your vendor if they plan to support the TMF RM exchange mechanism standard

TMF Exchange




Timeliness

“Article 57 states “the clinical trial master file shall at all times contain the

essential documents relating to that clinical trial.” The requirement “at all times” means that

the TMF should be updated, and completed in a timely manner.”

“[…] it is important, therefore, to keep the TMF up to date, with documents placed in the TMF

in a timely manner as this greatly assists the successful management of a trial by the

investigator and sponsor (or party to whom the sponsor has delegated its duties).”

“Filing essential documents at the investigator/institution and sponsor sites in a timely

manner can greatly assist in the successful management of a trial by the investigator,

sponsor and monitor.”

EMA

EMA

ICH




Big Issues• Terminology used in the guidance is vague and open to interpretation

• What is timeliness?

• What date determines timely completion?

Practical Considerations• Consider a process to define when TMF artifacts need to be in a TMF

• Establish methods for measuring timeliness and standards around dates

• eTMF should have a mechanism for detecting missing artifacts

• Most documents can be tied to a milestone

• e.g. Site Selected -> Site Initiated

• Compliance with protocol timelines, study plans established at trial start

Timeliness




Direct Access

“With reference to Article 57 of the Regulation, direct access to the TMF is expected.”

“Direct access includes all the systems that comprise the TMF as defined by the sponsor […]”

“The eTMF should allow review in an efficient manner, analogous to that possible with paper

TMFs.”

“Any training should be an option for the inspector to choose and is anticipated to be very

brief (taking no more than an hour).”

EMA

EMA

EMA

EMA




Big Issues• Systems are not well-adapted for inspector use (especially with minimal training)

• Many systems could hold TMF content and providing direct access to all systems becomes challenging

• How do you control access to inspectable content only?

Practical Considerations• Include a section in TMF plan for inspections

• Define which systems contain TMF content and plan for access in the case of inspection

• Establish whether inspector will have direct access (is there an interface for this provided by your

vendor?) or guided access (who will do it?) or will you provide a verified listing?

• Include requirements in your eTMF for inspector view

• For other systems, evaluate whether that capability exists, otherwise consider guided access

Direct Access




Record Retention

ICH E6: at least 2 years after marketing approval or at least 2 years since the discontinuation of clinical development of the investigational product.

Regulation in ICH countries

• EMA (EU): At least 25 years after end of trial

• MHLW (Japan): Until the day marketing approval is obtained or 3 years after date of premature termination or completion of the clinical trial, whichever comes later

• FDA (US): 2 years after marketing approval or 2 years after shipment and delivery of IP is discontinued

• Health Canada (Canada): 25 years after end of trial

• Swissmedic (Switzerland): at least 10 years after completion or discontinuation of the trial (15 years for implantable devices)

ICH

ICH




"Ensure the integrity of the data including any data that describe the context, content and structure of

the data. This is particularly important when making changes to the computerized systems, such as

software upgrades or migration.“

"Media used to store the data may potentially deteriorate or become obsolete, thus transfer to

an alternative would need to be considered. The media should be stored under appropriate conditions.

Any transfer or migration needs to be validated. The transfer of data to new media as technology

advances would need to be considered by the organisation."

ICH

EMA

Record Retention




Big Issues• How do you retain electronic records for 25

years? (Remember those floppy disks) • No real harmonization between RAs...

Record Retention




Practical Considerations• Define the plan for archiving at the beginning of a trial

• Define process for periodic verification of archived electronic records

• Follow ISO standards

• ISO 19005, Document management – Electronic document file format for long-term

preservation – Part 1, Use of PDF 1.4 (PDF/A-1)

Record Retention




Cloud Computing

NIST Definition: • A model for enabling ubiquitous, convenient, on-demand network access to a shared pool of

configurable computing resources (e.g., networks, servers, storage, applications, services) that can be

rapidly provisioned and released with minimal management effort or service provider interaction.




Ensure adequate controls in place to ensure reliability and confidentiality of the data.

Some key factors to consider• Validation documentation• Ability to generate accurate and complete copies of records• Availability and retention of records for FDA inspection for as long as records are required by • Archiving capabilities• Access controls• Secure, computer-generated, time-stamped audit trails of users’ actions and changes to data• Encryption of data at rest and in transit• Electronic signature controls• Performance record of the electronic service vendor and the electronic service provided• Ability to monitor the electronic service vendor’s compliance with electronic service security and the data integrity

controls

Cloud Computing

FDA




Big Issues• How do you ensure that whoever is holding your eTMF content in the cloud allows you to meet the regulatory

requirements around electronic records?

• Lack of guidance from the regulators with regards to cloud computing

Practical Considerations• Important to establish who is responsible for what (vendor, subcontractors, third parties) (quality agreements)

• Ask vendor how they meet 21 CFR part 11 requirements

• Ask industry colleagues how they’ve done it

• Perform due diligence – regularly

• Look for certifications like SOC and ISO

Cloud Computing




“In organizing the TMFs, it is essential to segregate some documents that are generated or held by the sponsor only,

from those that are generated or held by the investigator only, and vice versa.”

“The investigator TMF may be electronic with the system either provided by the sponsor, a vendor or health care

institution. A situation where all the investigator site records are sent to the external sponsor for uploading onto an

eTMF system, which the investigator then accesses via a portal, would potentially breach data privacy requirements

and give sole custody to the sponsor for source documents. Therefore, such a construct is considered unacceptable.

Remote access, i.e. access to investigator documentation at the investigator site from a different location by sponsor

personnel, to personal data of trial subjects in the investigator TMF, is unacceptable. Where a portal is used to provide

documents to the investigator, if this is not part of the investigator TMF there needs to be a mechanism to ensure such

documentation is filed in the official investigator TMF. Also, there should be an audit trail to demonstrate investigator

access to documents in the portal at the appropriate time.”

Site Documents/eISF

EMA

EMA




Big Issues

• Sponsor cannot hold certain site documents and vice versa

• Do sites really want another system?

• How can you ensure that sites are properly maintaining their ISF?

Practical Considerations

• Ask your vendor about the mechanism in place to segregate site only vs. sponsor only documents

• Evaluate eISF systems that may exist to see if they are a fit. Remember that the Sponsor cannot hold the ISF

for the site

Site Documents/eISF




“Evolutions in technology and risk management processes offer new opportunities to increase efficiency and focus on relevant activities. […] Advances in use of electronic data recording and reporting facilitate implementation of other approaches.”

“The essential documents for the trial may be supplemented or may be reduced where justified (in advance of the trial initiation), based on the importance and relevance of the specific documents to the trial.”

“As part of the validation a formal process should be in place for regular QC checks of digitised and indexed documents in the e-TMF. This would usually be undertaken on a sampling basis, including escalation procedures where errors occur beyond a pre-defined Acceptance Quality Limit (AQL). ”

ICH

EMA

Risk Based TMF

EMA




Big Issues• We don’t take a risk based approach today....• How do you demonstrate and measure quality?• Multiple vendors, multiple systems makes risk management challenging• Difficult to join the dots to fully understand the sequence of events

Practical Considerations• Define a plan for risk-based TMF review, consider:

• Study design and complexity• Number of vendors• Number of systems used containing TMF records• Assigning risk scores to document types based on process risk and other factors

• Ask your vendor if they have or plan to introduce risk based functionality for QC and risk identification• Think about how you can better organize information to better tell the story of what happened and

leverage this information to assess risk

Risk Based TMF




“The sponsor should ensure oversight of any trial-related duties and functions carried out on its behalf,

including trial-related duties and functions that are subcontracted to another part by the sponsor’s contracted

CRO(s).”

“The sponsor may choose to outsource duties and functions of the sponsor to a CRO. The sponsor remains

responsible for the trial and will need to maintain oversight, so access to the sponsor TMF (e.g. remote access

to an e-TMF) or at least to relevant documents from it will be necessary in order to discharge their

responsibilities effectively.”

“FDA recognizes that sponsors and other regulated entities may choose to outsource electronic services. […]

When these electronic services are used to process data for FDA-regulated clinical investigations, sponsors and

other regulated entities should consider whether there are adequate controls in place to ensure the reliability

and confidentiality of the data.”

ICH

EMA

Sponsor Oversight

FDA




Big Issues

• What is oversight?

• How do you demonstrate and measure it to provide evidence of oversight?

Practical Considerations

• Define process for sponsor TMF oversight in TMF plan

• Define methods for oversight for example, process for QC and QA of the TMF by the sponsor and

supporting documentation

• Define KPIs in service level agreements

• Avoid duplicate records available at sponsor and vendor levels – increases risk for error and

inconsistency. Use signposts and defined process for access instead.

Sponsor Oversight




State of the Union2Where are we now?




• TMF is changing – moving away from being a document repository and moving

towards being an information management system

• TMF is a gold mine of information which if leveraged in the right way can not only

tell a better story of what happened in the study but also provide more insight into

study risks

• The regulators seems to be moving quickly and not everything is 100% clear yet

State of the Union




• The future of eTMF will be more data driven, connected and holistic and will focus

on presenting processed based views of study activities

• Easier exchange of eTMF information and artifacts is on the horizon with the

soon to be released TMF RM Exchange Mechanism Standard

• Paper is starting to finally disappear and a new wave of more intelligent eTMF

solutions should be here soon!

State of the Union




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