2k Clinical Consulting, Inc.

5 Reasons Why QA Is Essential in Clinical Trials

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].

FDA vs EMA in Terms of GCP Inspections

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/.

Getting to the Core of the CAPA System – The Root Cause Analysis

You have just undergone an audit and discovered a gap in your process.  What’s the next step?  The key to inspection readiness is having an effective CAPA system that not only correct the issues but also prevent them from happening again. Only by identifying the root cause of the problem will you be able to prevent it from happening again.

When it comes to diagnosing the source of an issue in a fast-paced industry, speed is important. As a result, many departments rely on the tried-and-tested procedures of Root Cause Analysis (RCA) and Corrective Action Planning (CAPA) to identify and prevent problems. Here’s a closer look at Root Cause Analysis.

What Is a Root Cause Analysis?

Root Cause Analysis (RCA) is a technique for determining what, how, and why an event occurred so that preventative measures can be adopted. Data collection, root cause identification and execution are all part of it. To put it another way, RCA is a set of procedures that allows you to delve behind the surface of a problem to uncover causal pathways that lead to the problem’s underlying root causes.

What Are the Root Causes?

To comprehend fundamental causes, we must first comprehend what the issue is in the first place. A problem could be a divergence from customer specifications or another type of non – compliance at its most basic level.  The root causes of these issues are the precise, root factors that can be properly identified, are within the company’s authority to address, and result in effective solutions to prevent relapses.

How Are RCA and CAPA Connected?

The CAPA as discussed before,  is the action phrase, whereas if RCA is the subject. The root cause is what is causing the problem, and the CAPA is what will be done to fix it and keep it from occurring again.

The 5 Why’s in RCA

The 5 Whys is a simple yet powerful cause-and-effect method for determining the fundamental cause of a problem. You’ll begin by identifying the problem (RCA input), then query why each issue is happening until you find the root cause. Keep in mind that you don’t have to stop at five; in some circumstances, six or seven repeats may be necessary.

The Action Plan

The team must build suitable countermeasures or remedial activities after determining the root cause.  The team should also devise a strategy for putting the solutions into effect. The counter-measures can be divided into two categories:

  • Short-term Action Plan: Countermeasures that can be implemented quickly, usually in less than a week
  • Long-term Action Plan: Long-term or lasting solutions are usually more difficult to implement and may necessitate additional resources. All “long-term” action plans should be completed in less than one month. If not, they should be sent to the Continuous Improvement (CI) team for review.

Conclusion

By discovering the underlying cause and taking action to prevent it from reoccurring, the establishment of a comprehensive, well-planned Root Cause Analysis (RCA) methodology can be extremely beneficial to a department in terms of inspection readiness. Many of the lessons learned during a successful RCA can be applied to similar designs or processes.

Need to strengthen the Root Cause Analysis of your CAPA System? Contact us! We’d love to hear from you to discuss strategies!

 

References

  • Buchholz, V. (2019). What Went Wrong and How To Fix It.
  • Quality-One. (2021). Root cause Analysis (RCA). Quality. Retrieved September 10, 2021, from https://quality-one.com/rca/.
  • Wikimedia Foundation. (2021, July 13). Five whys. Wikipedia. Retrieved September 10, 2021, from https://en.wikipedia.org/wiki/Five_whys.

 

3 Surefire Ways your TMF can extend your Inspection

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:

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

Inspection Preparation Concepts for Clinical Research Sites

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…

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

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 regulationsLearning 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 inspectionsYou also need to prepare for and conduct a Lessons Learned session. 

  1. Prepare for lessons learned session – the preparation should be done in advancewhere 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. 

5Cs to Inspection Readiness Success (for Clinical Sites)

By Kimberly Kiner

Q: When is the best time to start preparing for an inspection?   

    1. After database lock 
    2. After the inspection announcement 
    3. After IND/IDE Submission 

‎A: If you answered C, you are correct. ‎‎ ‎‎ ‎‎Inspection Readiness is an ongoing process that starts at the beginning of the trial. ‎

We all know that inspections can be quite stressful; however, a stressful environment can be minimized with proper preparation and inspection readiness techniques.  This article will discuss the 5C IRS (Inspection Readiness Success) Model as one of the strategies that can be utilized as an inspection readiness technique for clinical research sites.

The 5Cs are: 

  1. Collect Information – In collecting information, it’s important to consider researching from both internal sources (e.g. prior audits, inspections and monitor visit reports) to determine existing gaps in your processes in addition to external sources (e.g. websites of regulatory authorities such as USFDA, EMA, Health Canada, etc.) to review guidance materials, requirements and expectations.

  2. Collaborate with the sponsor – Be proactive in utilizing inspection readiness tools and collaborating with the monitor & sponsor’s inspection team for additional support in preparing for inspections and implementing effective inspection readiness strategies.

  3. ‎Communicate with stakeholders‎‎ – ‎‎Communicate with internal stakeholders (colleagues, PI, monitor) to address gaps in study-related documentation to ensure that they‎‎ ‎‎are present, ‎‎complete‎‎ and accurate.‎‎ ‎‎ ‎‎ I‎‎t’s equally important to ensure that staff are properly prepared to communicate with external stakeholders (e.g. regulatory authorities) and able to interact ‎‎effectively ‎‎with the Inspector/FDA Investigator prior to, during and after the inspection.‎‎ ‎‎ ‎‎ ‎

  4. Correct via CAPA (Corrective and Preventive Action) PlansPart of having an effective Corrective and Preventive Action plan for each finding is to include all of the elements such as:

    • Root Cause – Why did this happen? Was it a systemic or isolated event? 
    • Correction – What correction was done to immediately resolve this finding?
    • Corrective Action – What will be your corrective action and how will you implement to ensure this finding does not recur?  For example, you may need need to createimproverevise SOPs and checklists/templates and retrain staff on the revised processes.
    • Preventive Action –  What are you checks and balances?  Incorporate preventive measures within a timeframe (e.g. 3- 6 months) to ensure similar finding(s) never happens again.  

  5. Conduct Compliance Checks –  Compliance checks involve the evaluation of the implemented processes from your CAPA.   Utilize checklists at frequent intervals to reveal gaps and determine what’s working vs. what’s not.  In addition, review findings from monitoring visits as gauge for compliance checks especially if time and resources are limited at your clinical research site.

Remember, inspection readiness is an ongoing process.  Incorporating an Inspection Readiness strategy, such as the 5C IRS (Inspection Readiness Success) Model, in your daily operations not only creates a culture of compliance, but also allows your site to proactively prepares for and contributes to the success of future inspections.  

Need a checklist for your site? 

Download our free Inspection Readiness Checklist today!