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Determining Relevant Correspondence in the TMF

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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:

  1. sequentially throughout the study (“file-as-you-go”),
  2. occasionally throughout the study, or
  3. 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

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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.  

TMF Building Blocks to Inspection Readiness Success

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An often-overlooked aspect of a clinical research study is the Trial Master File (TMF). As the backbone of every trial, the TMF houses all of the documentation describing all study activity in compliance with Good Clinical Practice (GCP) guidelines and approved protocols. With all of the moving parts involved in and outside of the TMF, it can be a constant challenge for all parties to keep up with. This is why it is so crucial to establish a foundation for success from the very beginning of a study.  

This article will discuss the building blocks of the Trial Master File in regards to how you and your team can set up, organize and manage an inspection-ready TMF.

How should you organize the Trial Master File?

Although there are TMF resources available such as the TMF Reference Model from Drug Information Association (DIA) and the general list of Essential Documents outlined in section 8 of the ICH E6 GCP guideline, it can be easy to lose track of documents without the proper TMF structures in place for your clinical trial. Overall, the TMF should be set up and divided into the following sections:  

  • Global/Core Files – This section contains documents used on a global scale. Trial-related, clinical or internal team reports, and clinical documents and templates are included here.
  • Country Files – This section contains country-specific documents. You can find documents from regulatory authorities and Ethics Committees, investigational product details, and country-specific documents and templates.
  • Local/Site Files – This section contains documents relevant to the sites participating in the study. There is usually documentation on Subject Information, site correspondence, monitoring, local laboratories, Institutional Review Boards/Ethics Committees, and site-specific investigational products or devices.

How do you manage the Trial Master File?

Management of the TMF can make or break a clinical trial. Without noting down study activity, we cannot prove that it even happened at all. While updating the TMF is not always the priority day-to-day, implementing measures and processes will help prevent any incomplete documentation or failed inspections in the future. Below are some strategies you can keep in mind for maintaining the TMF.

  • Training

First and foremost, everyone needs to be on the same page. From individual team members at a site to the CRO, each person and organization should understand the importance of maintaining the TMF and the procedures needed to do so. Make sure that the processes they are trained on follow the teams’ natural workflow if possible.

  • Clear Expectations

Even with the best training, sometimes we can go astray from protocol. The best way to keep everyone accountable is to have clearly defined roles, responsibilities, and expectations. Not only does everyone know what their part is in maintaining the TMF, but it also allows stakeholders to have an idea of how the study is progressing.

  • Self-Checks

Maintenance is not always enough when it comes to getting the TMF inspection ready. The team should also be conducting regular Quality Checks (QCs) of the TMF to ensure that it is up-to-date with all of the right documentation. Although time-consuming, it can make you more confident come inspection time.  

  • Bottom-line: Document Everything

At the end of the day, all of the effort put into managing trials will be in vain if it is not documented in the TMF. It’s not a matter of if you did the work, but rather, how you did it. Showing auditors a clear picture of the clinical trial with the documentation to back it up will make inspections easier for everyone.

Conclusion

By simplifying the organization and management of the TMF, you are also taking your team to the next level of enhancing your current TMF processes resulting in having a successful inspection from any regulatory authority.

Inspection Preparation Concepts for Clinical Research Sites

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The first thought that typically comes to mind when you hear about an upcoming FDA inspection at your site is the logistics– where to meet, document review, and your facility’s condition.  There are however, other factors to keep in mind for both on-site and remote inspections.

This article will briefly cover the basic principles of a GCP inspections and what clinical site staff should expect and keep in mind for future inspections.

FDA Investigators (commonly known as Inspectors) regularly visit clinical research sites to conduct inspections and ensure GCP requirements are being followed.  In fact, according to FDA’s inspection metrics, almost 800 BIMO or Bioresearch Monitoring  inspections are conducted  at clinical research sites every year (with the exception of the pandemic in year 2020).

What to expect

Whether an FDA Investigator conducts an on-site or remote inspection, he/she will need to show his/her credentials and show an FDA-482 prior  to discussing the inspection’s purpose, scope and  number of days according to the size and complexity of the trial(s) being inspected.

In general, the first day of inspection will also require the review of pre-inspection records, site files and subject files.  Interviews will also be conducted with the study personnel, such as the study coordinator(s) and the Principal Investigator to determine compliance to the regulations, protocol/investigational plan and other study-related procedures.

At the end of each day, the inspectors will do a summary of findings, as well as a general verification of their checklist to confirm if inspection criteria were fully covered and all requested documentation received.

The most important aspects that FDA Investigators  focus on are patient safety and data integrity. They will look at patient consents, adverse event/experience reporting, and anything that could potentially jeopardize the patient’s safety. They also ensure data integrity by confirming the absence of data transcription errors  and compliance to  the regulations, protocol and other study requirements according to CPGM (Compliance Program Guidance Manual) for Clinical Sites.

What to keep in mind

  • Plan Accordingly – Keep a checklist available to ensure documents are inspection-ready. site staff are adequately prepared and technology is properly working for provided access and sharing documentation (especially for remote inspections).
  •  Practice Interview Skills –During the interviews, it is important to inform your staff about the Do’s and Don’ts of interviewing including how to answer the questions asked by the inspectors. For example, all site staff should be prepared to discuss topics such as:
    • Training – Safety-related, Protocol, Case Report Form
    • Delegation of study-related tasks/PI Oversight
    • Subject recruitment
    • Informed consent process
    • Source documentation
    • Data entry
    • Investigational product or device handling

Interviewees only need to answer the question directly with no additional information. Moreover, if you don’t know the answer to a certain question, it is acceptable to say that you don’t have access to that information at the time and that you will get back to them with an answer later.

  • Don’t get defensive/ask questions – Be sure that none of your staff are getting defensive with the FDA inspector as this might come back to haunt you.
  • Ask for Clarification – If you need clarification or have questions about the findings reported by the FDA inspector, it is totally acceptable to point them out. However, defensive behavior is never a good idea.

Key Takeaway

Inspections are an important aspect of clinical research trials.  A proactive approach and consistent preparation from clinical site personnel at the start of a trial, results in a successful inspection at the end.

Need an Inspection Preparation checklist for your site?  Feel free to download our free Inspection Preparation Checklist as a preparation tool.

 

 

 

Location Matters…

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What’s wrong with this picture?

On a typical workday, you may see nothing wrong with this picture…but place an FDA Investigator or other regulatory Inspector in this room, and you may it see differently. I’ve had the opportunity to work as an FDA Investigator working in the GxP (primarily GMP) world.  I left that career and transitioned over to the industry (AKA ” the other side”) in GCP starting out as a Clinical Research Associate (CRA).  

As an FDA Investigator inspecting all types of manufacturers, I was accustomed to reviewing documents in immaculate, spacious conference rooms.  When I became a CRA monitoring clinical sites, however, I had a rude awakening and was quickly humbled by my designated monitoring space. There were no spacious conference rooms…sometimes no room at all.  With some sites, I was placed in a small cubicle.  With other sites, I sometimes shared the busy desk of either the Principal Investigator, Sub Investigator or Study Coordinator. 

But the most memorable experience was when I was placed in the break room /copy/printer room where I shared a table with documents and binders from other trials and was entertained by interesting (and sometimes incriminating) conversations from site staff. 

At that point, I couldn’t help but reminisce on my prior career as an FDA Investigator thinking “Boy, would I have a field day if I were an FDA Investigator placed in this room!”

 But I’m no longer an FDA Investigator…I’m on the “other side” now, training others on audit/inspection readiness and providing tips on how they should prepare and set up appropriately for an inspection. 

Important tips to know when it comes to set up is to adequately prepare your staff and facility including inspection and support rooms.

FACILITY AND STAFF PREPARATION

When preparing the facility, for an on-site audit or inspection, select a private area, or conference room that has a phone and, a copy machine for document requests.  It is important that other areas such as work areas and printing rooms are clean and free of loose documents. 

Finally, support areas or affiliated departments such as the pharmacy and or laboratory should be assessed to ensure all documents and staff are inspection-ready.

Also post designated signs throughout nearby areas notifying others of the inspection to ensure all nearby conversations are minimized during the inspection.​

INSPECTION ROOM VS SUPPORT/WAR ROOM

The Inspection Room should be a quiet, private and paper-free located near the Support/War Room.  This room should also be set-up with computers and screens for the FDA Investigator to review records and electronic systems used in the trial.​

The Support/War Room which is a combination of clinical site and sponsor support, should be equipped with working electronics (such as email, printer, Instant Messaging) and dedicated to providing all needed documentation for the inspection.

KEY TAKEAWAY

In order to fully prepare for an audit or inspection, you must consider the rooms in your facility as part of readiness planning and preparation.  After all, LOCATION MATTERS!

 

How To Implement Lessons Learned From Regulatory Inspections

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This article will highlight some of the steps you can take to implement lessons learned and optimize your company’s policies and procedures in terms of compliance and alignment with the regulations. 

Different regulatory agencies perform frequent inspections to ensure compliance with pertinent study-related processes and their respective regulations. Learning lessons from these regulatory inspections and implementing them as part of your processes or Quality Management System will tremendously help you in the future. 

Implementing the lessons learned from regulatory inspections 

Immediately after an inspection, there should be a process in place for implementing lessons learned. Here are the steps to implement lessons learned from regulatory inspections: 

1.Identify Lessons Learned 

Identifying comments and recommendations made during recent regulatory inspections is valuable for future inspections. You also need to prepare for and conduct a Lessons Learned session. 

  1. Prepare for lessons learned session – the preparation should be done in advance, where you organize areas that prevent discrepancies and missing information. You should have standard criteria for each clinical study you are conducting. 
  2. Lessons Learned Session – this step focuses on identifying the successes and failures of your processes as it relates to your trials, which also includes some recommendations on how to improve performance for future regulatory inspections. 

Ask the following questions: 

  • What went right during the inspection? 
  • What went wrong during the inspection? 
  • How can we improve for future inspections?

2. Document Lessons Learned 

After capturing lessons learned, you should document everything into a comprehensive report that summarizes the inspection and what everyone can do to improve in the future. You can also conduct interviews with your team members to discuss what went right and what went wrong.  Finally, you can share the report with your team members and executive team emphasizing how this will help you improve performance and readiness for future inspections.  

3.  Analyze Lessons Learned 

Analyzing and organizing the lessons learned from regulatory inspections is also a key step to improve your preparedness in the future. You can continue to conduct meetings to assess when training will be implemented based on new or updated processes. 

4.  Archive Lessons Learned 

Once you have finished the steps listed above, you need to organize and file the lessons learned documentation along with other reports from prior audits and /or regulatory inspections.  While everyone should have access to the documents in your facility, you need to place some focus on keyword research since it will help you get access to the wanted lesson.  

5.  Retrieve lessons learned 

The final step of the Lessons Learned process, especially as new trials arise, is to retrieve the documentation and reflect on successes and failures.  Focus on how your team can maximize successes and minimize and failures in preparation for the next trial.    Having a collection of lessons learned documents is a great asset that serves as powerful inspection readiness tools and allows you and your team to prepare for upcoming clinical trials in addition to future inspections in the most effective way possible. 

Takeaway message  

Preparing yourself and your team before an inspection is vital to ensure that everything goes smoothly. Learning from previous lessons and implementing your new knowledge is indispensable to achieve the goal of continuous improvement and successful inspections. 

If you have any questions or concerns, please do not hesitate to share your thoughts in the comment section below. 

Our Mission and Purpose

The mission of 2K Clinical Consulting, Inc. is to ease the burden of GxP compliance and to transform the effectiveness of professionals and compliance systems worldwide.

Our History

2K Clinical Consulting, Inc. is the vision of former FDA Investigator, Kimberly Kiner, who empathized with facilities and sites that struggled with understanding and complying with regulations. After years in the field, Kimberly transitioned into the private sector and acquired international experience in compliance, monitoring and study management while she worked for pharmaceutical and invitro/medical device companies as well as CROs. This work experience is what sparked her desire to work as a consultant for organizations such as the Association for Clinical Research Professionals and the Society of Clinical Research Associates. Kimberly later went on to train providers such as Compliance Online and Fx Conferences. This exposure became the gateway to connecting with other experts and teaching professionals resulting in an engaging experience for clients that closes the gap in best practices within the realm of compliance.