“If it is not documented, it is not done”. So, documentation is a vital part of the clinical trial process. eTMF - Challenges, Opportunities & Trends Speaker: Betsy Fallen December 10, 2015
eTMF - Challenges, Opportunities & Trends · eTMF - Challenges, Opportunities & Trends Speaker: Betsy Fallen . December 10, 2015. Essential Documents are the evidence that demonstrate
Essential Documents are the evidence that demonstrate Investigators, Sponsors, and Monitors have met the expectations of Good Clinical Practices (GCPs) and related regulations. The documentation stored in the Trial Master File is becoming increasingly digitized driving eTMF adoption across the industry. The trends in industry best practices, regulations and technology will change the models of today and the associated business processes. The careful planning and astute attention to the environment will ensure awareness and timely decision making. It is evident that the changing landscape of partnerships, outsourcing, regulations and guidelines will affect the roles and responsibilities of stakeholders including authors, reviewers and users of eTMF. This webinar will examine the impact these changes would bring to document management using eTMF. The Sponsor/CRO, Monitors and Investigator/Site roles will be assessed for opportunities in the transition to eTMF trends. Attention will be paid to the anticipated evolution of industry best practices, regulatory guidance and the underlying technology innovations. The action plans will be outlined to optimize changes to eTMF implementation & management processes while ensuring efficiency and compliance. The change management proposals to encourage endorsement and adoption will be discussed.
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MakroCare’s eTMF solutions help clients minimize cumbersome paper document management and routine pain points of TMF Management
MakroCare eTMF Service • Advisory & consulting support for eTMF
Compliance• Experienced document management specialists• Implement right processes as per regulation/SOPs
for seamless compliance• Facilitates cross-functional co-ordination for
documents & audit readiness anytime
DDi SmartTMF • Offers all time “audit and inspection” readiness• Provides real time metrics & reports that facilitates
"Oversight”• Enhances documentation quality and integrity• Improves productivity of document management
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Meet our Speaker Betsy Fallen
• Until recently, Betsy was with Merck where she spent several years in the clinical operations area
• Developed expertise in Trial Master Files and eTMF/eISF along with associated metrics as part of the organizations including MCC
• Currently engaged with industry standards and best practices organizations such as the SAFE-BioPharma Association and the DIA TMF Reference Model working group
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• Describe the potential of eTMF for impact on the businessprocesses currently utilized by regulators, researchers and patients
• Recognize the benefit and challenges anticipating eTMF trends would bring to business processes
• Identify the opportunities future trends may facilitate for increased compliance and patient safety
What are we going to cover
Presenter
Presentation Notes
Welcome to the webinar. Today we will describe the how the electronic trial master file may impact on the business processes used by the stakeholders who are tasked to create access and maintain this repository. We will review the benefits and challenges that all of these business processes bring to our organizations. We will also look at some of the anticipated trends that are on the horizon that will impact our business processes and look for some of the opportunities that we will have to enhance patient safety as well as ensure compliance
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Background
DefineTrial Master File
• “Essential Documents are those documents which individually and collectivelypermit evaluation of the conduct of a trial and the quality of the data produced. “
• “Trial master files should be established at the beginning of the trial, both at theinvestigator/institution’s site and at the sponsor's office. A final close-out of a trialcan only be done when the monitor has reviewed both investigator/institution andsponsor files and confirmed that all necessary documents are in the appropriatefiles. “
• “Any or all of the documents addressed in this guideline may be subject to, andshould be available for, audit by the sponsor’s auditor and inspection by theregulatory authority(ies). “
Investigator Site File (ISF)• Subset of the Essential Documents at a clinical site for which the investigator
In order to establish the foundation for the trial Masterfile we're going to talking specifically about the electronic trial Masterfile. FIRST we’ll look at defining what the trial masterfile is. I’ve given you the link at the bottom so that you can access the complete ICH guidelines for yourself. Here I've highlighted some of the specific quotes that a really pertinent to today's discussion. essential documents encompass all the documentation that are contained in the trial Masterfile. these are what together permit the valuation of the conduct of the trial that means this is the roadmap, the recipe for how the trial is expected to be executed. The second quote here really emphasizes the timing of the growth of the trial masterfile over the course of the trial that should be established & maintained. in today's typical organization this is decentralized and primarily in paper this is really difficult to prove to any regulator inspector auditor that you've actually done this on an ongoing basis. the last comment that I thought was extremely relative here was that these documents or should be have to be available for inspection by auditors or regulators. The systematic storage of the Essential documents adds challenge in that it isn’t as simple as unlocking a cabinet. What you would also find in ICHE6 is a list of essential documents and notation on whether those are to be stored in the Sponsor or Site files, or both. Interesting, there are 54 items on that list, which I’ll reference later in the talk. The last point I went to make on this slide is the reference to investigator site file. This file, the ISF, is a subset of the overall trial Masterfile. these are the documents that are required to be maintained at the clinical site. the investigator owns these, they control these and they're responsible for these. if anyone asked for these documents it is the investigators responsibility to produce these documents in a timely manner. so we'll talk about this a little bit but this really has significant of impact in today's business processes as they change with regard to regulation and technology.
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Why are Essential Documents required
Legislation / Regulations• Inspections
• Part of the regulatory authorities evaluation of a marketing application
• “For cause” – suspected or known violation• Legal
Patient Protection:Both as investigational subjects and
as consumers for a marketed product
Presenter
Presentation Notes
With regard to the trial master file or the electronic trial master file, and the content (the central documents which are in them) why do we collect them? the reason is that they required by law. they are required by the regulations be FDA EMA or Japan. they're required to have essential documents maintained for the duration of the trial and for some time afterward. Afterwards that's also sent by the regulations as well as some guidance documents and reflection papers by the NHRA these records must be available for inspection there's couple different kinds of inspections. There is a defined duration by which these records need to be retained by either sponsors or sites. The retention of the essential documents will not be covered today. That is a complicated topic by regulatory or legal assessment that could be the topic of it’s own webinar. For the protocols that have been submitted to a regulatory authority as part of the marketing application supporting an investigational product request for approval, the regulators will typically plan for a certain percentage of the clinical sites to be inspected to ensure that the data was collected appropriately. If there are concerns for the processes under which the data was collected, the impact may be to further asses the trial without the site data and in the most serious cases, exclude that data from a final analysis which may jeopardize the application. There is also a second type of inspection that may be done and this is for cause. this is maybe because there's a suspected are known violation something has been reported something has shown up in another trial perhaps in there looking for a wider opportunity for possible fraud or patient impact. Ultimately, these documents will protect patients, both during the investigational stage of development and as a marketed product.
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POLL QUESTION
• What is your organization’s plan for electronic TMF implementation?1. In next year2. In next 2-3 years3. No plan in near future4. Already using eTMF
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Transitioning: Decentralized TMF to eTMF
http://tmfrefmodel.com/
Presenter
Presentation Notes
I created this graphic to contrast the trial masterfile currently in place and what's trending as we speak. Today, we can expect to see in the electronic trial masterfile in the left. it's certainly a disparate collection of paper files, some electronic content, some media. this all constitutes a trial masterfile it's not easily identified if it's complete if it's comprehensive if you put a piece of paper in those files is not necessarily going to be guaranteed that it The graphic on the right represents the simplified electronic trial masterfile as well as the empty shelves that you hopefully have once you have everything into the trial master file. In a formal eTMF system, the repository is cloud based. Here I have represented as the organizational structure of the 11 zones for the structure that's been defined by a dia community this is known as the TMF reference model. this is the organization of documentation which is typically been adopted by electronic files systems to organize the documentation. Anecdotely, regulators have noted they have asked if this is being used> offers familiar organization. If you recall the ICH E6 document noted 54 documents, in the reference model tool, there are 252 artifacts.
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View Study
Presenter
Presentation Notes
To share an image of the Makrocare SMART TMF, here you can see the organizational structure reflecting the Reference Model. Selecting The folders down the left side, reveals the artifact on the right along with some of the metadata associated with the artifact. This metadata will be discussed later in my talk as it is an important component of an eTMF.
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Single Repository• All Essential Documents stored in one system• Format, size and access not common• May cause more issues than setting up several
Multiple Repositories• Based on file type – functionality may need to be retained
(e.g., Data or SAS Files)• Based on access/security
• Regulatory Correspondence, including Marketing Applications may have unique access
Remember:All must be identified, accessible, managed appropriately
The eTMF: Is it One or Many “e”?
Presenter
Presentation Notes
Now that we talked about moving all the documents from disparate systems into a TMF, lets touch on reality. The TMF typically does not encompass just one location. A few repositories usually houses the collection of all documents. if there's a single repository it has to be able to be accessible to all manage all formats and that's not always possible. every organization typically has more than one repositories which are considered the TMF that stores based on the file types and the ability to control access. d the security for example if you have a marketing applications part of your regulatory correspondence is going to be significant and different
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Is long termpaper storage an option?
Presenter
Presentation Notes
I wanted to share what is frequently a little known fact and that is the stability of long term retention of paper at off-site storage facilities. Not all is as secure as it may seem. If the records are required to be kept, storage options such as Iron Mountain have been compromised in the past.
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POLL QUESTION
• According to the 2015 DIA Trial Master File Reference Model Survey, what percentage of respondents reported currently using an electronic Trial Master File?
1. 85%2. 67%3. 44%4. 29%
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7%
44%
14%
17%
What is the status of your organization's eTMF?
2015 TMF Survey
18%
Actively Planning
Actively Building/Implementing
Not Considering
We currently use eTMF / eISF
Evaluating
http://tmfrefmodel.com/
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Key Benefits of eTMF to Business Process
Benefit driven by• Audit trail• Metrics – assessment of documents and metadata
• Completeness• Quality• Timeliness
• Systematically controlled access
Presenter
Presentation Notes
Now lets talk about the business processes. As any lean, efficient and compliant process is assessed, unless the assessment is a manyual review of a managed index, the metadata associated with each artifact will be key to reveal characteristics of the artifact and the overall health of the TMF. The systematic evaluation that results in reports, graphs and alerts, will offer value that a disparate or paper system is not able to.
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Who contributes to, accesses or benefits from the Trial Master File?
Regulators• Inspections• Monitoring
Researchers (Sponsors & CROs)• Records eTMF content: documents, owners, inspectable location• Monitors content for evidence of protocol compliance• Oversight of outsourced efforts by protocol, program or functional
role• Evaluate for Mergers & Acquisitions or In-licensing Opportunities• Audits
Sites: Investigators, Coordinators, Patients• Owner of eISF• Monitors all site Essential Documents for updates• Patient records retained
Presenter
Presentation Notes
Before we get into the business processes around the trial Masterfile, let's talk review the key roles of those who will use and access the files. first you have the regulators… these individuals will access the documentation to execute inspection. they may do real-time monitoring such as risk based monitoring. The sponsor or CRO are the owners of the sponsor repository. you would have researchers such as the clinical operations team assessing site ready, progress of IRB reviews or timeliness of safety report review. Field monitors may be performing a reconciliation of the sponsor files to the site files in advance of a visit. For outsourced trials or when monitoring a functionally outsourced role, a sponsor could be performing a high level of assessment to ensure the CRO is compliant and meeting deadlines. The third stakeholder are the investigators, site staff and patients. Performing the tasks of the trial and providing care to their subjects will be enhanced by the prompt access to updated information, including safety information. The personal information, some of it financial, and protected health information as part of trial masterfile it is required to be filed, but the security of managed access is critical. I’ll touch on the topic of security a bit later.
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What process impact does an eTMF introduce?
Regulators• Increases efficiency
• Minimum training• Standard organization (Best Practice
recognized in many eTMFs)• Reduce time or days required for
inspection• Paper can extend an inspection if a document
is not at hand• Audit trail• Digital document assessment
• Requires tools for accessing eTMF(s)• Image QC becomes a factor
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Audit Log
Presenter
Presentation Notes
Supporting the audits and use of the assigned or systematically identified metadata, this screen print of an Audit log clearly indicated the history of a document. This is information that is helpful but raises the responsibility of the owners of the documents and the system too ensure the business process clearly documents expectations and that the execution of those processes aligns with them.
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eTMF Implementation
• Increases efficiency• Reduce time required • Identify issues in a timely manner
Protocol Performed
Protocol w/Data Submitted to Regulatory Authority
Sponsor and Site Inspections to
Ensure Compliance
Protocol Performed
Protocol w/Data Submitted to Regulatory Authority
Sponsor and Site Inspections as needed
Future Trend: Real time inspection by metrics, reports, direct review
Before eTMFImplementation
After eTMF
Implementation
Presenter
Presentation Notes
With refinement to systems and access management, this may be the progression to a future state. The blue bar represents todays steps, protocol completed, marketing application submitted for review, followed by sponsor and site inspections. One opportunity that might be available is shown in the green bar. If the appropriate system was in place and the access was role based to include the regulators, the comprehensive TMF, including site and sponsor, could be remotely monitored contemporaneously. Any deviations from process might be identified and behaviors corrected promptly, improving patient safety and increasing the quality of the data.
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DID YOU KNOW?According to the FDA Investigations Operations Manual, Sponsors and site staff should NOT expect FDA to request direct access to systems (‘hands on keyboard’) during inspections.
Sometimes it’s not regulations that drive process….The FDAs Investions Operations Manual (IOM) dictates who the FDA will access the sponsor or site documentation. Do not be surprised if you are asked to have a super user or SME put hands to keyboard and follow their direction. Be prepared with a role based access account that will be used. I wouldn’t be surprised if this changes soon, or is in actuality not being followed. Other agencies, expect they will ask for a bit of training then askyou to step away.
When a Sponsor has contracted with a CRO to perform a clinical trial andwill receive Essential Documents electronically at the end of the trial, theSponsor should ensure the documentation includes the audit trail.
1. True
2. False
POLL QUESTION
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POLL QUESTION
When a Sponsor has contracted with a CRO to perform a clinical trial andwill receive Essential Documents electronically at the end of the trial, theSponsor should ensure the documentation includes the audit trail.
1. True
2. False
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Document Uploading (audit trail)
6 /72 Exl Pharma TMF Summit, London Oct 2015 Andy Fisher, Senior GCP Inspector, GCP Inspectorate, MHRA
INSPECTION
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What process impact does an eTMF introduce?
Researchers• Offer enhancements for electronic document authoring
• Managed cycle time (global, partnerships)• Expense optimization (reproducing, shipping)
• Study Monitoring• Mitigate manual assessment of completeness, quality and timeliness• Enhance sponsor oversight of CROs, Partners
• Archival• Paper more resource intensive• Mitigates paper document integrity
• Optimally diminish inspection findings
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Steps a Protocol takes to TMF – Paper
Drafted
Reviewed Revised
Finalized Filed in Sponsor
TMF
Copied /Returned Copied
MailedFiled in
ISF
Challenge: Each step includes copying, adding wet signatures, image QC & distribution
$$
$$ QTime
Presenter
Presentation Notes
Take the steps to create and manage a protocol, for example. All of these steps , at one time were done in paper. I see that today it is a hybrid of paper and electronic. With paper, at any point in the process, a misplaced record, a lost page can disrupt the process. With the addition of an electronic template, review and approvals can be facilitated electronically Ultimately final repository, will retain the inspectable copy, both for the sponsor and the site. You do have to ensure that your SOPs match your process. For example, where a wet signature was once required, an email approval or electronic/digital signature may replace it. Where paper may have been the inspectable medium previously, perhaps the electronic version is now the inspectable copy. I’ll touch on this again a bit later.
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Summary Dashboard
Presenter
Presentation Notes
Just as each document shows in lists in some displays, the overall document count by category can also be produced as in this graph. This type of report can be evident of a situation that requires a closer review. It’s also an opportunity to compare and contrast across studies. To view one study at a more granular level…..
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Investigator Dashboard
Presenter
Presentation Notes
….this slide reveals the exact numbers in each category. This may be assessed as part of a Service Level Agreement where at a defined date or milestone a predetermined percentage of documents should be approved or less than a certain percentage of documents may be in the missing category.
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Review Page
Presenter
Presentation Notes
Here we have the MakroCare SMART TMF displaying the action step of electronically noting review comments on a document. Eliminating the requirement for a wet signature results in a
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POLL QUESTION
• For in-house trials, how does your company manage TMF/eTMF currently?
1. Internally as a task assigned to a Clinical Operations Role2. Internally by TMF-dedicated SME team3. Externally as a functional outsourced role to TMF
vendor
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Who uses the Trial Master File and what impact does an eTMF introduce?
Investigators, Coordinators, Patients • If documentation is available to investigators, prompt awareness of safety
• Systematic recognition of site document review• Centralized access• Ensure Investigator control• Enhanced by elimination of paper
• Interface with other contributors (e.g. IRBs)• Adoption of electronic consent forms
Challenge: The electronic Investigators Site File control is the same as paper. These are the investigator’s records and the audit trail should reflect that.
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Change Management
• Awareness • What problem are we trying to address?
• Can relevant inspection or audit findings be shared?• Consider actual Warning Letters posted on FDAs website
• Communication• Reasons: Why?• Benefits: What’s in it for us?• Details: When? where? who is involved? Cost?
• Skills Assessment Technology needs and willingness to learn?
• Education/Training• Feedback
• Opportunities for named or anonymous comments provide outlet
Presenter
Presentation Notes
Change Management has to do with supporting the people through transition. There should be a program to assess and involve all stakeholders. As the transition from paper TMF to eTMF, every role at the sponsor, CRO and site should be included in the new way to do business. One of the components that are not listed here is Sponsorship. There needs to be senior level endorsement and engagement
• Efficient resource utilization• Focused oversight of CROs and functionally
outsourced roles• Timely access to time sensitive information• Systematic assurances of delivery• Opportunity for optimized space utilization• Prompt process and behavior correction
Presenter
Presentation Notes
To summarize the advantages, opportunities that I see with the adoption of an eTMF… -resources, people, budget, real estate would all ne managed more efficiently -the opportunity to execute and demonstrate the execution of CRO or FSP oversight will be clearly documented - Timely access sensitive information such as safety reports will be evident and can be clearly documented -Any process not providing the desired outcome or perhaps not being followed can be corrected promptly
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Challenges of Future Trends
• Change Management• Electronic Retention >> Managing Ongoing digital access• Need for controlled access to sensitive information
• Protected Health Information• Financial references
• Meeting global and local requirements for privacy• Ownership transfers not a simple handoff• Technology obsolescence
Presenter
Presentation Notes
With innovation comes challenges, some never before considered …dealing with people, manage expectations… …how and where and how long will the records need to be retained? Who pays and who controls? …in an electronic system, access to PHI or financial data must be managed….the headlines are full of security breach reports …no longer can a program be sold and a collection of paper be boxed and sent off…. …technology assessments will need to be made and digital handoffs be documented …in very much the same progression as Beta, VHS and likely soon to be CD/DVD, where the eTMF resides and the file format they are in wull need to be retained to b=continue to be readable and accessible
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Action Plans
• Every clinical trial should have an Essential Document Plan• Identify each document owner and inspectable source
• Roles and responsibilities should be defined and kept up to date • Security, Security, Security
• When contracting programs, protocols or tasks, define expectations
• Review all SOPs and related business processes to ensure accuracy
• Include institution SOPs• Monitor regulations and inspectors best practices
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