Trial Master File Archives - 2k Clinical Consulting, Inc.

FDA vs EMA in Terms of GCP Inspections

August 25, 2023October 13, 2021 by The 2K Blog Team

The national and global regulations for conducting clinical trials involving human participants are known as Good Clinical Practice (ICH-GCP). They include not only quality criteria, but also regulatory guidelines to ensure that all newly created pharmaceuticals and medical devices have been clinically shown to benefit the health of the public. The FDA and the EMA are two of the most important regulatory authorities involved in ensuring patient safety and data integrity, and here is some information about both.

FDA vs EMA

The United States Food and Drug Administration (USFDA) is a division of the United States Department of Health and Human Services. All investigative product and approved products (drugs and devices) sold in the United States are reviewed, approved, and regulated by the FDA both domestically and internationally. The European Medicines Agency (EMA), on the other hand, controls the drug development process for all European Union member countries.

How do the FDA and EMA work differently?

Inspection Focus:

FDA Investigators will spend some time looking at generic processes, but their main focus will be on research activities. The overall approach will be to follow the Bioresearch Monitoring Program guidelines and check conformity on each study. While the EMA will analyze study details in their trial master file (TMF) review, their Subject Matter Expert (SME) interview will focus mostly on general processes.

Trial Master Files (TMF):

There is no particular FDA mandate for organizations to develop a trial master file in the United States, but if the regulatory body wants ICH GCP to be followed, then a trial master file must be created and maintained.

Inspectors from the EMA, on the other hand, will conduct a thorough and comprehensive assessment of the TMF and, with rare exceptions, will prepare to browse without assistance. TMF review will normally take up major time during the inspection. Moreover, these organizations anticipate that the majority of study documents will be accessible directly within the TMF and will be recorded in a timely manner. If a TMF is ready for an EMA inspection, it is probably ready for any other significant agency as well.

Document Review:

According to the EMA’s inaugural documents, the agency’s main goal was to recognize the importance of improving patient-reported health-related quality of life (HRQOL). The EMA’s patient-reported outcomes (PRO) advice focuses on numerous domains for generalized HRQOL assessment, whereas the FDA’s focus is on symptom-specific measurements. This distinction can be seen in the pazopanib approval documentation. While the EMA included HRQOL data from pazopanib phase III studies in its assessment, the FDA statement makes no mention of this objective.

Conclusion

The two most influential regulatory agencies, USFDA and EMA, assure us that we can trust the industry as their respective accomplishments become more transparent in improving current processes and safeguarding patients and the clinical industry’s future.

References

CTA. (2019, January 11). Observations from GCP sponsor inspections. Clinical trials arena. Retrieved October 11, 2021, from https://www.clinicaltrialsarena.com/comment/how-to-prepare-for-gcp-sponsor-inspections.

EMA. (2021, August 10). European Medicines Agency. Retrieved October 11, 2021, from https://www.ema.europa.eu/en.

NCBI. (n.d.). FDA in PMC. National Center for Biotechnology Information. Retrieved October 11, 2021, from https://www.ncbi.nlm.nih.gov/pmc/funder/fda/#:~:text=FDA%20is%20responsible%20for%20protecting,manufacturing%2C%20marketing%2C%20and%20distribution%20of.

NIRH. (n.d.). Trial Master File. Trial master file. Retrieved October 11, 2021, from https://www.ct-toolkit.ac.uk/routemap/trial-master-file/.

Shalby, M. (2018, August 3). Good clinical practice: FDA vs. Ema. LinkedIn. Retrieved October 11, 2021, from https://www.linkedin.com/pulse/good-clinical-practice-fda-vs-ema-michaela-shalby/.

Key Aspects of an Inspection Ready TMF

August 25, 2023June 22, 2021 by The 2K Blog Team

Having a complete Trial Master File (TMF) is the highest priority for sponsors in terms of providing an accurate picture of the affiliated clinical trial. This article speaks about key aspects and techniques to implement in order to have an inspection-ready TMF.

Key Aspects of an inspection ready Trial Master File

Important aspects of having an inspection-ready TMF is to:

✓ Include documentation which is able to ‘tell the story’ of the trial.

✓ Contain a detailed time period, coexistent in time of facts and observation.

✓ Have an electronic source which documents are clearly stated.

✓ Update regularly and implement proper Quality Check (QC) techniques.

QC techniques

Five QC techniques to implement to ensure an inspection-ready TMF are to:

Look through the auditors eyes – Reviews are made from the source of information provided. Research requirements and expectations of health authorities in order to properly look at the data from an auditor’s perspective.
Collect Information-All documentation from Core and Country levels such as the Protocols, Investigational Plans, Informed Consents, etc. should be thoroughly reviewed as the foundation QC’ing data from local site documentation.
Site Sampling – Site Sampling is being able to look into all records based on a sample taken from a number of high enrollers, noncompliant and terminated sites.
Review and Cross Check – Reviews are taken on bother paper and electronic Trial Master File. Each has different mode by which it is reviewed:

For Paper files, review and cross check:

Original hardcopies– all original documents must be properly checked if they are correct and signed accurately.
Filing & Organization – ensure that there are no missing or misfiled files that can cause delays during an audit or inspection.

For an electronic TMF, review and cross check:

eTMF Study Access – review current project team list to verify correct access to study files
eTMF Filing & Organization – Check for duplicates and errors in Indexing (or naming) and uploads

Follow up to Resolution – It is imperative to follow up all issues to resolution which means having an effective the root cause and all other corrective and preventive actions in place, including steps on how any investigation should be taken, and who should be involved and the process.

Overall, it is critical to be knowledgeable about key aspects of industry standards and regulations. An inspection ready TMF takes proper planning, as noted in our article Planning for TMF Success, and effective QC measures as discussed in the following Trial Master File training sessions:

The “Audit-Ready” TMF: Concepts & Strategies (basic)
The “Audit-Ready” TMF: Tools &Techniques to effective QC Reviews (intermediate)- COMING SOON
The TMF Challenge: Part of the IRS (Inspection Readiness Survival) Series (advanced)-COMING SOON

3 Surefire Ways your TMF can extend your Inspection

August 25, 2023June 7, 2021 by The 2K Blog Team

The Trial Master File (TMF) is the backbone of the clinical trial. It consists of essential documents which not only enable the conduct of a clinical trial, but also enable the evaluation of the quality of data produced.

One of the questions asked at the beginning of an inspection is: “Where and how are your documents stored?”. It is expected that all responsible parties know the location(s) of all paper/hybrid, and electronic documents that comprise the TMF. Most importantly, it is expected that the TMF is readily accessible and audit-ready.

The reality is…this is not always the case. In most cases, the TMF is often forgotten and becomes a disorganized “pile of files”. As a result, inspections can be extended for this reason.

In fact, MHRA stated that that 35% of inspections were extended and required extra days particularly due to critical findings of TMFs.

Three (3) critical findings and surefire ways a TMF can extend your inspection are:

1. Lack of Access – The majority of time, the full TMF is not readily available or accessible to inspectors causing a delay in document review.

2. Poor Indexing – Oftentimes, the person designated to the TMF has issues locating documents during inspections due to poor indexing.

3. Incomplete/Missing Files – This is self-explanatory. Files that are inaccurate, incomplete or missing/misfiled can certainly cause a delay. Furthermore, uploading last minute documents to the eTMF (electronic Trial Master File) is a red flag as inspectors can see the download date and time of each document.

Sounds familiar?

Well, this can all be prevented with proper planning, as noted in our article Planning for TMF Success, and effective QC measures as discussed in the following Trial Master File training sessions:

How to Increase Visibility for an Inspection-Ready TMF

June 7, 2021May 24, 2021 by Kimberly Kiner

The Trial Master File (TMF) stores all essential documents pertaining to the conduct of a clinical trial in compliance with Good Clinical Practice (GCP) guidelines. It is the “backbone” that tells the story of a clinical trial at every phase from start-up to closeout and is one of the most scrutinized objects during an inspection.

Ensuring that the Trial Master File is inspection-ready and visible to all participating parties is no easy task and requires consistent effort. In this article, we will detail Trial Master File setup and how you can increase its visibility.

Setting up the Trial Master File

Having a system that is easy–to–access, clear, and transparent for all parties involved is the goal for your TMF. While TMFs have traditionally been in paper format, it is now the norm to use an electronic trial master file or eTMF.

Digital systems can provide a centralized storage system, security, project management, audit trails, and numerous tools to track a study’s progress efficiently. Every TMF system needs to contain all essential documents as outlined in section 8 of the ICH E6(R2) GCP guideline. However, the work doesn’t stop there.

Don’t forget that TMF-maintenance is an ongoing process that should accurately reflect the clinical trial at any particular stage. Another factor to consider as you set up the TMF is training. Having procedures and a Trial Master Plan in place ensures that your team is routinely maintaining the TMF and appropriately communicating with the CRO, sponsor study teams, and investigational sites for up-to-date records.

Increasing visibility of the Trial Master File

Your TMF should be inspection-ready regardless of what phase you are at in the clinical study. The nature of the eTMF system lends itself to increased visibility, but its perpetual state of change can also dampen this effect if not properly maintained. Consider the following tips for enhancing the visibility of an eTMF:

Prepare documents ahead of time – while eTMFs are great for storage, the essential documents can easily get lost and misfiled if the filing system is unorganized and maintained by staff at different locations. To avoid having inaccessible documents during an inspection, train staff on maintenance, proper filing, and procedures emphasizing the importance of compliance in the system.
Integrate eTMF systems to facilitate collaboration – one of the benefits of an eTMF is its ease of access from anywhere at any time. However, sometimes software conflicts limit visibility and prevent Sponsors or CROs from filing documents properly. When implementing an eTMF, look out for systems that can easily integrate with other platforms to facilitate collaboration and exchange of documents between study stakeholders.
Update performance metrics – on top of storage capabilities, eTMF systems can also track key performance metrics: Timeliness, Quality, and Completeness. Like the documents, these numbers also need to be updated to be useful for improved future performance. These metrics can provide all parties involved insights into how current processes are running and how they can be improved.
Make the inspection as easy as possible for the Inspector – part of facilitating an inspection is to make the inspector’s job as easy as possible, so every detail counts. Make sure that they can easily access documents, view documents in their original size and perhaps on multiple screens, as well as annotate in the system if possible.

Conclusion

Increasing visibility of your TMF can seem like a daunting task, but it doesn’t have to be. With the introduction of eTMFs, it has never been easier to conduct clinical trials. With the above tips in mind in setting up and enhancing visibility in the eTMF, you are on your way to having an inspection-ready TMF!

Determining Relevant Correspondence in the TMF

May 12, 2021May 12, 2021 by Kimberly Kiner

Correspondence in the Trial Master File (TMF) is imperative to keep all parties abreast of the details involved. In order to keep all information relevant and the entire TMF streamlined and efficient, it is necessary to decide what is important, applicable, and mandatory.

Current health authority regulations require that organizations retain relevant correspondence. This includes correspondence that is essential for reconstruction of activities, decisions in clinical trials and other important information. Other correspondence, like irrelevant correspondence, should be evaluated through a formal process to decide on whether it adds value or contributes to the story of the trial.

Correspondence through email is a common and necessary way to convey information pertaining to the clinical trial; however, they can quickly overwhelm the entire process and create informational chaos when it comes to filing. While emails are the quickest way to communicate to sites about trial updates, it is crucial to be able to determine the relevancy for a more streamlined filing process.

Determining Relevance

There are factors that can help you determine relevant correspondence to file in the Trial Master File. Individual organizations can expand on these criteria to clarify the terms within their own context and define their individualized filing approach in their Trial Master Plan.

They can choose to file correspondence either:

sequentially throughout the study (“file-as-you-go”),
occasionally throughout the study, or
after the study has been completed.

The following are considered relevant correspondence for the TMF:

Agreements – Any communication of agreements made between two or more parties or individuals pertinent to the study.
Relevant and significant discussions – Any discussion relating to changes made should be recorded and filed.
Protocol violations – All information regarding violations of the existing protocols set in place for the research must be tracked and filed.
Trial conduct – Information regarding the conduct of actions relevant to the clinical research is to be recorded and filed. For example, if the subject is eligible, and allowance of rescreening.
Adverse event reporting – All occurrences of serious issues associated with the clinical research should be filed.

The Responsibility of Filing

Once it is determined that an email or article is deemed important, the responsibility of whom should file it comes into play. To avoid duplication of information or deletion of relevant details, it is important to lay out clear instructions so that everyone is on the same page. Therefore, drafting concise guides with best practices that are laid out clearly and assigning these tasks to the most efficient members of the team becomes paramount.

Conclusion

Often in a clinical trial, circumstances can change quickly. This requires the study team to adjust their trial conduct accordingly. Circumstances, such as the COVID-19 pandemic, forced teams to communicate more via email and other online technologies. With inboxes being inundated with reams of information, it is more imperative to have a streamlined filing process, especially when it comes to TMF correspondence.

Planning for TMF Success

April 27, 2021 by SysAdmin

Tackling the Trial Master File (TMF) can seem daunting at times. With so many moving parts and documents, it can get more difficult to manage as a clinical trial continually progresses. However, the TMF is essential as it tells inspectors the story of a study from beginning to end.

Keeping the TMF up-to-date is crucial due to this very fact, but teams often struggle with getting it audit-ready due to disorganization and inconsistencies. Common challenges with TMFs (paper and electronic) are:

Storing documents in several locations, making them difficult to access during an inspection.
Limited collaboration between sponsors and CROs especially if there are different filing processes, systems, or incompatible software.
Metrics can help provide key insight into organizational performance measures but are also another source of frustration in TMF management because of the need to be updated regularly

These challenges can be addressed with setting up a plan, specifically, a TMF plan which could help streamline processes.

What is a TMF Plan?

The TMF Plan details every aspect of TMF management. It sets boundaries and specifies who is responsible for specific TMF sections. It could contain a TMF Master List or TMF Table of Contents (TOC) that outlines procedures such as deadlines for each document, study reports, or specific milestones unique to each organization.

The TMF Master List could also reference the Standard Operating Procedures, which describes each TMF document. Other types of information you might expect to see in this plan include TMF review frequency.

What is the purpose of the TMF Plan?

Transparency is key to building a high-quality TMF. The TMF Plan provides all information, data, and processes relevant to TMF management. This results in a complete TMF come inspection time and sets expectations for all parties involved. It is meant to keep sponsors, CROs, vendors, and other TMF stakeholders in the loop on everything from how documents are filed to the location of the TMF.

What is the format of the TMF Plan?

Having a TMF Plan is not required, but it helps keep everyone on the same page. It is especially important if the sponsor and CRO are both adding content and maintaining the TMF. Each organization will have its own approach as to how TMF management will work, and it generally helps to have TMF Plans that address the following TMF points:

Official location
Management procedure documents
Breakdown of tasks & responsibilities
Content filing processes
Training and access management
Structure
How to add content
TMF activity documents
Formal archive plan

The above will largely vary based on your organization’s needs, but it is a solid starting point in formulating your new TMF plan.

Conclusion

Some of the biggest obstacles in a clinical trial are putting together an audit-ready TMF and having the metrics to back it up. You can avoid any of the unnecessary stress of inspections by having everything laid out from the start.

Having a TMF Plan in place gives your team and other stakeholders a micro and macro view of the TMF management process, from content procedures to specific deadlines when TMF deliverables are due. As a result, the TMF plan keeps everyone on track throughout the clinical trial and sets everyone on the right path for future successful inspections.

FDA vs EMA in Terms of GCP Inspections

FDA vs EMA

How do the FDA and EMA work differently?