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Preparing For Pharmacovigilance FDA Inspections

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The concept of pharmacovigilance—derived from the Greek and Latin ‘Pharmakon’ (medicinal substance) and Vigilia (to keep watch)—emerged in earnest among physicians and other health experts almost 200 years ago. Initially, the practice amounted primarily to letters and reports written by physicians on the safety and effectiveness of various drugs given to their patients.

Pharmacovigilance inspections (Good Pharmacovigilance Practices, GVP) are designed to assess compliance with the legally prescribed mandatory reporting of adverse drug reactions in clinical trials as well as spontaneous reports. 

The three (3) most common findings noted from FDA’s Post-marketing Adverse Drug Experience (PADE) inspections according to the Bioresearch Monitoring (BIMO) Fiscal Year 2021 Metrics  are:

  • Failure to develop written procedures for the surveillance, receipt, evaluation, and reporting of post-marketing adverse drug experiences
  • Late submission of 15-day Alert reports
  • Late submission of the annual safety report

This article will list ten (10) key areas or documentation to have ready for FDA in an upcoming GVP inspection.

What To Have Ready for an Inspection

  1. Written Procedures
    You must develop, maintain, and follow written procedures for the surveillance, receipt, evaluation, and reporting of post-marketing safety information. This includes procedures for managing safety information with contractors and business partners, as applicable.
  2. Individual Case Safety Reports (ICSRs)
    ICSRs describe one or more adverse experiences related to an individual patient or subject. A valid ICSR contains a suspect drug, an adverse experience, an identifiable patient, and an identifiable reporter.
  3. Scientific Literature Reports
    Regarding scientific literature reports, ensure that there is documented evidence of:
     Scientific literature reviews and the frequency of each review.
     Submission of expedited ICSRs for adverse experiences obtained from the published scientific and medical literature that are both serious and unexpected
    • Foreign Post-marketing Adverse Experience Reporting
      For participating affiliates, subsidiaries, contractors, and business partners outside the United States, ensure the following:
       There are written procedures that address the surveillance, receipt, evaluation, and reporting of adverse experiences.
       There is documented submission of serious and unlabeled (i.e., unexpected) adverse experiences to the FDA within 15 calendar days.
    • Solicited Safety Data
      Solicited safety data arises from organized data collection systems, which may include patient assistance programs, patient support programs, physician engagement programs, or any active solicitation of information from patients or providers, when contact between the sponsor company and the patient or provider is predictable in the context of a specific program.
    • Aggregate Safety Reports
      For each approved application or biologics license, FDA requires the submission of Periodic Reports, which describe safety information obtained during the reporting interval. The reporting interval is quarterly for the first three years following the approval of the application or license, and annually thereafter, unless FDA instructs the sponsor otherwise.
    • Contractor Oversight
      Oversight of outsourced services may include a broad range of activities to ensure that all outsourced services and activities associated with post-marketing safety are performed according to applicable FDA regulations.
    • Electronic Submissions
      Determine if safety report submissions are in an electronic format that FDA can process, review, and archive, as required.
    • Waivers
      Any post-marketing safety waivers from the regulatory requirements must follow applicable procedures and terms of the waiver.
    • Recordkeeping
      For approved drugs or biologics, ensure that all records containing information relating post-marketing safety reports (whether submitted to FDA) have been maintained for a period of 10 years, or for combination products, the longest retention period applicable.

    Conclusion

    Post-marketing safety data collection and adverse event reporting is a critical element of the Food and Drug Administration’s post-marketing safety surveillance program for FDA-regulated drug and therapeutic biologic products.  Incorporating the FDA requirements and guidance into your inspection readiness program contributes to the success of your GVP inspection.

    The Benefits of Storyboarding in Clinical Research Trials

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    As part of a sponsor’s inspection readiness activities, storyboarding is a crucial step that provides a solid framework for addressing challenging or important areas of noncompliance via corrective and preventive actions. With the aid of organizational and risk assessments, sponsor companies should be able to pinpoint issues and utilize storyboards to systematically discuss the implementation of action plans with inspectors as requested during an inspection.

    Storyboard Benefits

    Utilizing storyboards has various benefits.  The top five benefits include the following:

    1. They offer a structure for formulating concise content that the inspection team can convey reliably.
    2. They are particularly beneficial in circumstances where an organization has gone through a transition or considerable change, for closing gaps that have already existed, and in other exceptional cases of self-identified compliance.
    3. They point out the corrective measures taken to guarantee patient safety and maintain data integrity.
    4. They assist in removing ambiguity, potential disagreement, and pressured decision-making while responding to inspection questions about challenging and perplexing clinical trial components.
    5. They lessen the possibility of issues occurring during an inspection as a result of several facilitators or SMEs accidentally giving conflicting accounts of what happened, and the steps taken to address associated problems or gaps.

    Storyboard Tips

    Being proactive and starting development when a problem or situation emerges can save a ton of time and work later on when attempting to put together a summary later. Therefore, it is a recommended practice to generate storyboards as early as possible.

    The following are useful tips regarding a storyboard:

    • A storyboard should be utilized as a tool to assist the facilitators in making sure that important information is accurately and succinctly communicated, and that those informing inspectors are on the same page.
    • The location of pertinent supporting paperwork should be listed on a storyboard so that facilitators can respond to inspection demand swiftly.
    • Storyboards should not be lengthy things of the past with background or unnecessary material, but rather brief and to the point. They are designed to contain minimum amount of information necessary to properly respond to an inspection request.
    • A storyboard’s content can be discussed verbally with an inspector but storyboards themselves should not be shared or mentioned because they are not meant to be discussed in full during an inspection.
    • Storyboards shouldn’t include statements that unintentionally encourage facilitators to disclose information that an inspector might not have otherwise asked, as this could raise further questions and create confusion or ambiguity.

    Conclusion

    In conclusion, storyboards can offer the foundation required to communicate important information in a clear and simple manner with assurance and in synchronization across all departments of the organization, making the inspection readiness process considerably simpler for all parties involved.

    References

    Gwizdak , S., & Marshall, M. (2020, December 10). 4 ways to Adapt Your Inspection Readiness Framework in a post Covid-19 World. Halloran Consulting Group. Retrieved August 1, 2022, from https://www.hallorancg.com/2020/06/19/4-ways-to-adapt-your-inspection-readiness-framework-in-a-post-covid-19-world/#:~:text=Storyboarding%20is%20an%20important%20activity,critical%20aspects%20of%20a%20study.

    HealthResearchBC. (2020, October 27). Regulatory update: Clinical trial storyboards. Clinical Trials BC. Retrieved August 1, 2022, from https://www.clinicaltrialsbc.ca/regulatory-update-clinical-trial-storyboards/

    LifeScienceLeader. (2020). 09.28.20 — bringing clarity to Regulatory Inspection Readiness & Facilitation. 09.28.20 — Bringing Clarity To Regulatory Inspection Readiness & Facilitation. Retrieved August 1, 2022, from https://www.lifescienceleader.com/doc/bringing-clarity-to-regulatory-inspection-readiness-facilitation-0001

    5 Reasons Why QA Is Essential in Clinical Trials

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    The coordinated and impartial review of all clinical trial-related activities and records is known as quality assurance. In the case of a clinical study, the quality assurance department has a wide range of responsibilities. Quality Assurance (QA) departments frequently aid in inspection readiness by establishing investigator site selection guidelines and identifying service providers to be audited, such as laboratories, packaging and supply chain vendors.

    The Ongoing Challenge

    The continuous monitoring of data collection processes and data management policies at every level of the study is an ongoing challenge in managing the quality of clinical data and maintaining compliance. This includes the following:

    • verifying that the data collected during the trial is consistent with the procedure (case report form [CRF] vs. protocol)
    • ensuring the validity of the data in the CRF and data acquired in source documents (CRF vs. source documents)
    • guaranteeing that the analyzed data correspond to the CRF data (database vs. CRF)

    This confirms the need for QA involvement in clinical trials specifically in terms of inspection readiness.

    Reasons Why Quality Assurance (QA) is essential

    1. Time Saver

    While continuous monitoring during a clinical trial is a taxing task, it can save you from wasting hundreds of hours rectifying shortcomings within the trials at a later stage. Errors recognized in their initial stages are easier to modify to achieve desired outcomes. Whereas, delays can worsen the problem in clinical trials and inevitably push back the desired result, which can hinder the inspection readiness process.

    1. Money Saver

    While many believe that investing in quality assurance from the get-go is not only time-consuming and costly, it is quite the opposite. Errors during the trial stage lead to millions of dollars lost during the production stage and major delays in inspection readiness, which can further add to the cost. Sometimes dropping the trial before entering the production stage due to a lack of quality assurance become inevitable.

    1. Boosts Client Confidence

    Businesses that are known to ensure quality assurance are more likely to retain trust and confidence from clients and customers alike. During clinical trials, clients are more likely to follow the lead and trust the process when their standards of expectations align with the trials working. When boosting clients’ confidence, it is essential to highlight both the “whats” and “hows” of the trial, and quality assurance helps deliver the “hows” of the trial to keep your clients’ mind at ease.

    1. The Backbone of Consistency

    When it comes to clinical trials, it is of utmost importance that each drug produced be of the same quality to prevent ill-desired outcomes. In clinical research, the quality assurance process ensures internal consistency by scheduling regular operational checks at each level of the trial process and data collection processing to validate trial procedure compliance and data validity.

    1. Leads to Accountability

    When quality assurance is the working foundation of a clinical trial, each individual involved plays a vital role in ensuring that they deliver top-notch results in making the trial a success. Hence, the need for excellence permeates every aspect of a company in which quality assurance is at play.

    Conclusion

    Maintaining integrity and precision during a clinical trial is an ongoing, dynamic process that is the key to inspection readiness. This continuing process necessitates modifying processes and effectively conveying these adjustments to all investigators and support staff. This is why quality assurance involvement is essential and a key component to the clinical Quality Management System (cQMS) overall.

    Need to strengthen or supplement your QA component? Contact us for a free consultation! We would love to hear from you to discuss strategies!

     

    References

    • BROWN, C., 2019. Price Check: How to Cut Costs in Clinical Trials. [online] Anjusoftware.com. Available at: <https://www.anjusoftware.com/about/all-news/insights/cut-costs-clinical-trials> [Accessed 8 April 2022].
    • JLI Blog | Global Training & Education Provider. 2018. Quality Control and Quality Assurance in Clinical Trial | James Lind Blog. [online] Available at: <https://www.jliedu.com/blog/clinical-trial-quality-control-assurance/#:~:text=In%20clinical%20research%2C%20quality%20control,and%20reliability%20of%20the%20data.> [Accessed 8 April 2022].
    • Manghani, K., 2011. Quality assurance: Importance of systems and standard operating procedures. Perspectives in Clinical Research, 2(1), p.34.
    • Parashar, P., 1995. Patient Satisfaction – A valid tool of quality assurance (C. Q. I). J Family Community Med, 2(2), pp.7-8.
    • The Important Site. 2022. 10 Reasons Why Quality Assurance Is Important – The Important Site. [online] Available at: <https://theimportantsite.com/10-reasons-why-quality-assurance-is-important/#:~:text=Quality%20assurance%20is%20a%20process%20all%20organizations%20should,who%20could%20be%20with%20the%20company%20or%20independent.> [Accessed 8 April 2022].
    • Valania, M., 2006. Quality Control and Assurance in Clinical Research. [online] Applied Clinical Trials Online. Available at: <https://www.appliedclinicaltrialsonline.com/view/quality-control-and-assurance-clinical-research> [Accessed 8 April 2022].
    • WCG Avoca. n.d. Inspection Readiness: What is it and how do we get there?. [online] Available at: <https://www.theavocagroup.com/inspection-readiness-what-is-it-and-how-do-we-get-there/> [Accessed 8 April 2022].

    Key Aspects of an Inspection Ready TMF

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    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:

    1. 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.
    2. 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.
    3. 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.
    4. 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
    1. 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

     

     

     

     

     

     

     

     

    How to Increase Visibility for an Inspection-Ready TMF

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    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: 

    1.  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.  
    2. 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. 
    3. 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.  
    4. 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!  

    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.