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How Changes in ICH E6 (R3) Guidelines are Changing the Future of Clinical Trials

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ICH E6 (R3) Guidelines for Good Clinical Practices (GCP) have been a work in progress to put forward changes to the previous R2 version.  The overall purpose is to revise principles that account for ethical trial conduct, participant safety, and clinical trial outcomes that may be reliable. The ICH E6 R2 Guidelines for GCP consists of three key components:

  1. The overarching principle that will apply across the board
  2. Annex 1
  3. Annex 2

Annex 1 currently reflects the principles in E6 (R2), with necessary updates and modifications. While Annex 2 contains additional information that should be considered in the case of non-traditional interventional clinical studies that are not included in Annex 1.

Besides Annexes 1 and 2, the modifications in R3 consist of 12 major principles.  These 12 principles heavily focus on conducting clinical trials based on ethical principles, designing and conducting research that ensures patient rights, safety, and well-being.

Moreover, the principles highlight the need to acquire informed consent where participants are aware of all the trials. Subjecting the clinical trial to an objective review is another critical principle, along with ensuring that all trials adhere to the requirements based on the latest scientific knowledge.

Additionally, the principles highlight the importance of conducting the trial by an expert within the field and the necessity to include it in the scientific and operational design and execution of clinical trials. There is also an emphasis on designing the trial so that it’s comparative to patient risk and trial results while also ensuring that it’s clear and concise.

R2 vs. R3 What is The Difference?

R2

R3

Risk-based approach – The focus of E6 (R2) was on a balanced, risk-based approach to clinical trial design and execution.

Risk-based approach -ICH E6 R3 is intended to promote this notion while also encouraging interested parties to incorporate this approach.

Technology – E6 (R2) isn’t entirely equipped to deal with new technology.

Technology – The rising usage of electronic data sources and risk management procedures is addressed in E6 (R3).

Principle/Annex – R2 consisted of the overarching principle and annex 1.

Principle/Annex – R3 has revised the overarching principle and annex 1. Moreover, there is an addition of annex 2.

Is Clinical Research Industry Going to Face New Challenges?

Any change can bring about challenges; however, the gravity of the challenges depends on the quality design of the trial(s) currently in place. There is an evident need to ensure the reliability of clinical trial results. Without this, all the resources used to accomplish the findings would result in a loss of millions of dollars. This is precisely why the ICH E6 R3 has emphasized using Risk-Based Quality Management (RBQM) and Risk-Based Monitoring (RBM).

Many of the methods and technologies that researchers are already using in clinical trials will be simplified by the new ICH advice, especially when it comes to risk-based monitoring (RBM). The industry may anticipate guidelines on remote evaluation and observation, as well as a technical design that is flexible enough to accommodate both existing platforms and future developments, assuring trial integrity while removing the effort of confirming non-critical evidence.

Conclusion

Although many clinical researchers have yet to get accustomed to the ICH E6 R3 or implement it, the clinical importance of applying these guidelines will streamline research and produce more accurate and reliable results. Moreover, ICH E6 R3 will ensure inspection readiness ensuring no hindrance to clinical trials, which is why immediate implementation of ICH E6R3 guidelines are truly beneficial.

The process of building quality into the design of a trial can be arduous without the sound quality management system (QMS) in place.  Don’t have the time to ensure your system has the quality that exceeds compliance to the ICH E6 R3 standards?  Contact us and let us help you implement compliance strategies and a streamlined process for your QMS prior to the rollout! 

 

References

CITI Program. 2021. ICH Releases Draft Principles for GCP | CITI Program. [online] Available at: <https://about.citiprogram.org/blog/ich-releases-draft-principles-for-gcp/> [Accessed 15 March 2022].

ICH, 2019. Final Business Plan ICH E6(R3): Guideline for Good Clinical Practice. [online] Available at: <https://database.ich.org/sites/default/files/E6-R3_FinalBusinessPlan_2019_1117.pdf> [Accessed 15 March 2022].

ICH, 2021. ICH-E6 Good Clinical Practice (GCP). [online] Available at: <https://database.ich.org/sites/default/files/ICH_E6-R3_GCP-Principles_Draft_2021_0419.pdf> [Accessed 15 March 2022].

Mauri, K., 2021. Rewriting the Rules: How to Prepare for ICH E6 (R3). Pharmaceutical Outsourcing, [online] Available at: <https://www.pharmoutsourcing.com/Featured-Articles/579132-Rewriting-the-Rules-How-to-Prepare-for-ICH-E6-R3/> [Accessed 15 March 2022].

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

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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.

 

FDA’s CAPA Checklist for Medical Devices

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Since the year 2010, the most prevalent FDA audited observations in the medical device business have been “insufficient corrective and preventative action procedures.”  Its recurrence as the most common issue year after year indicates that many device firms have problems with their CAPA (Corrective and Preventive Action) systems, both known and unknown.  While the instant conformity risks are clear, those that leave firms open to major quality system flaws that can fester and spread beneath the radar of their quality management system (QMS) put patients and organizations at risk.

FDA publishes its own monitoring guide. It lays out the precise objectives for inspectors when reviewing a medical device CAPA system and supporting paperwork. Additionally, it also assists manufacturers in meeting the broad standards for effective CAPA.

What is the FDA CAPA Checklist for Medical Devices?

  1. Check if the CAPA system procedure(s) that satisfy the QMS regulation’s requirements have been identified and assessed.
  2. Check to see if the right sources of product and quality concerns have been uncovered. Ascertain that data from these sources is examined in order to ascertain current products and the quality issues that may necessitate remediation.
  3. Check to see if any product sources and quality data have been identified that may reveal unfavorable trends. Ascertain that the statistics from these sources are analyzed to identify possible product and quality issues that may necessitate intervention.
  4. Put the information management system to the test. Examine the data received by the CAPA system to ensure that it is complete, accurate, and reliable.
  5. Check that proper statistical approaches are used to detect recurring quality issues (if necessary). Check to see if analysis results are compared and contrasted across different data sources in order to discover and develop the scope of the product and manage any quality issues.
  6. Check to see if the procedures for failure investigation are being followed and determine whether the level of investigation is appropriate to the significance and risk of the nonconformity. Check to see if failure investigations are carried out to find the root cause (where possible) and if there is a system in place to prohibit the distribution of defective investigational devices.
  7. Determine whether or not suitable steps have been taken in response to serious product and quality issues uncovered through data sources.
  8. Determine whether corrective and preventive measures were effective and whether they had been checked or validated before being implemented. Confirm that corrective and preventive interventions have no negative impact on the final product.
  9. Check to see if remedial and preventive actions for quality issues were taken and recorded.
  10. Assess whether information on quality issues, as well as corrective and preventive measures, was adequately communicated, including for management review.

Conclusion

After evaluation of the CAPA process for devices, it is important that device firms narrow the gap between regulatory expectations and existing processes. This ensures that the devices are aligned with an FDA-compliant CAPA system. 

Need to strengthen your CAPA System? Contact us! We’d love to hear from you to discuss strategies!

 

References
The FDA Group. (2018). What The FDA Expects From Your CAPA Process. The FDA Group. https://www.thefdagroup.com/blog/what-fda-expects-from-your-capa-process.
Rodriguez, J. (2016). In CAPA In The Pharmaceutical And Biotech Industries: How To Implement An Effective Nine Step Program. Essay, Woodhead Publishing.

 

Important Aspects of Vendor Management Oversight

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An FDA inspection can be triggered by a variety of factors with submission of an application for product approval as one of the most popular factors.   With the increasing need to outsource to clinical research vendors, inspections of sponsor companies tend to focus on vendor management and oversight as one of areas of the clinical QMS (Quality Management System).  

The Importance of Vendor Management

Vendor Management is important because it can help you mitigate risks by reducing specific risks concerning operations and hidden costs from the vendor. Secondly, maintaining quality vendor management allows you to keep track of the vendors’ performance against the contract. Lastly, it’s not easy to come across good vendors for clinical settings. You must maintain your relationship with them to ensure the process remains efficient.

Vendor Management Oversight that You Should Keep In Mind:

To ensure business continuity with your key vendors, you’ll need a good vendor management process in place, as well as a documented plan for dealing with any concerns that develop.

A well-designed vendor managing process framework has seven key points:

  1. Determine which vendors need to be kept an eye on: These should always include your key and high-risk vendors, but they can also include other significant (but lower-risk) partnerships.
  2. Define the metrics you want to track: Assessments should comprise both quantitative and qualitative indicators.
  3. Make a list of your data sources and organize them: Questionnaire survey, procedures and policies manuals, SOC and audit reports, and third-party data intelligence technologies, to mention a few, can all be used to collect managing data. Make sure you have the data sources needed to input the types of indications you’ll be tracking. 
  4. Make a list of your SMEs (Subject Matter Experts):  When it comes to SMEs, they are the people who have the particular knowledge you’ll need to assist with certain elements of managing. Experts in project management, CRO and laboratory partnerships are particularly common.  
  5. Assign roles and duties clearly: While the person who controls the vendor relationship should be in charge of managing their vendors, there are many additional SMEs (Subject Matter Experts) involved in the process. Make sure to spell out who is responsible for what and when. 
  6. Establish mechanisms for escalation: It’s crucial to know which issues need to be escalated and what alternatives you have for addressing them when difficulties arise throughout the vendor managing process (which they always do).  Extending your due diligence, upgrading contingency measures, or even changing (or terminating) the contract are all options. The types of issues that require escalation and the methods you can use should be defined in your framework. 
  7. Taking advantage of technology: Finally, using technology to monitor vendors makes the process a lot easier. This includes your vendor management system as well as active managing tools that allow you to access external data sources.

 Conclusion

Regardless of the number of vendors you work with, efficient vendor management is a critical aspect of inspection readiness. To build an efficient strategy that will guide a collaborative relationship with vendors, you must first grasp the benefits and challenges of vendor management. To guarantee that your vendors give maximum value to your organization, supplement your process with vendor management best practices.

 

 

The Importance of a Clinical Quality Management System (CQMS)

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There has never been a better time to be in clinical research. From constant scientific innovation to being a part of a community of academic experts, there are seemingly endless opportunities to grow. While it all might seem exciting from the outside, organizations still face some internal challenges.

One such obstacle is the current clinical quality management systems (CQMS) in place at many start-ups or small firms. Their QMS are often not in line with global regulatory authority regulations or are deficient in the level of documentation needed to reconstruct and defend every aspect of clinical trials.

This can be fixed by having the basic quality systems embraced at every level of the organization in order to set the foundation for internal compliance and vendor oversight. In this article, we’ll discuss in detail about what the CQMS is, its key elements, and why it is important to implement in your organization.

What is a Clinical QMS vs QMS?

Every organization has a blueprint by which it operates under called the “quality system”, also known as the “quality management system” (QMS). It is a dynamic mechanism that overlooks and aims to improve core processes at maximum efficiency. The goal of the QMS is to provide a high-quality product at the lowest cost. In action, the QMS implements specific concepts, standards, methodologies, and tools to achieve quality-related goals.

On the other hand, the CQMS is a quality system more specific for clinical research and study management. It helps manage documents, processes, quality events, audits, and many more activities that occur throughout a clinical trial. More specifically, this system facilitates activities across the Clinical Quality and Clinical Operations sectors to improve efficiency, promote risk mitigation and risk management practices, and expedite drug development and delivery.

Key Elements of a Clinical QMS: Quality Management System Solutions

When setting up and implementing a CQMS, these are the key elements that should be highlighted:

  • Any processes should be well-defined prior to documentation. The organization should then determine the level and detail of procedural documentation that is needed to describe these processes. Procedural documents should detail policies, standard operating procedures, working instructions, etc.
  • Resources, Roles and Responsibilities. Both material resources and staff should be described in this part of the CQMS. Staff members should have clear roles and responsibilities that will directly affect operations and quality of outcomes. Leadership should be proactively managing resources on a consistent basis.
  • This includes collaborations, such as joint product development or outsourced activities. An organization has to understand the needs, expectations, limitations, and risks that will be carried out in such partnerships.
  • Risk Management. While you cannot predict every scenario that will happen, a risk management process will allow an organization to better predict such situations and prioritize resources to address the most significant risks that do arise.
  • Issue Management. This type of framework gives an organization the ability to quickly identify, investigate, assess, elevate, and communicate significant issues. Ideally, it should work in a way that issues will not recur and continue to improve the quality of clinical studies.
  • Knowledge Management. Knowledge is critical to the success of an organization’s performance. A knowledge management framework allows information to be applied by employees faster.
  • Documentation Supporting Achievement of Quality. There should be an appropriate level of documentation to back up the risks and significance of a clinical trial activity that will satisfy quality objectives and stakeholder requirements.

Important Benefits of QMS

An effective QMS system will result in better outcomes across all areas of your organization. Some of the most important benefits of a QMS include:

  • Identifying and improving processes
  • Improving patient safety in clinical trials
  • Providing a consistent framework for regulatory authorities
  • Streamlining clinical trial processes
  • Assuring data integrity
  • Reducing delayed studies
  • Resolving repetitive quality issues
  • Lowering costs

Conclusion

One of the reasons why some organizations struggle to achieve quality results is because of the lack of a framework that could help them better guide their processes and performance. A CQMS empowers organizations to define, learn, and improve upon every aspect of their process not only to improve performance and outcomes, but to also meet different stakeholders’ expectations. Implementing a CQMS will enhance an organization’s performance and inspection readiness and will ultimately facilitate the approval of investigational products.

 

Steps on Implementing a Clinical QMS

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By Afifa F. – 2K Clinical Consulting, Inc. 

 There is a popular saying in quality management that if you do not have the process written down, then it probably didn’t happen. Just like any other business, Clinical trials must have a management system as well. This needs to be well-conceived  as well as systemized.  

 What is a QMS in Clinical Setup? 

QMS are standardized procedures with guidelines. These particular guidelines are the backbone for all procedures to be carried out. A clinical quality management system (CQMS) is meant to keep track of all the records, activities, tasks, processes, important events, interactions, inspections, and training that must be administered and controlled during the study’s lifespan.. 

 What are the Benefits of QMS in a Clinical Trial? 

The Clinical Quality Management System program provides improved patient safety by enhancing quality, ensuring data security, reducing clinical trial bottlenecks, and bringing products to the market faster. 

 QMS Implementation Steps 

The following steps must be covered to effectively implement Clinical QMS: 

  1.  Mapping and Defining Your Process  – The production of process maps will compel the associated clinical trial members to visualize and define its processes. They will determine the connection pattern of those operations to be carried out during the process. Process maps are essential for determining who is responsible. Lastly, they help to clarify the flow of the clinical trials execution. 
  2.  Defining the Clinical Trials Quality Policy – Objectives are required in all quality management systems. Each employee must recognize the impact they have on quality. Your quality policy influences your quality objectives. It’s quantifiable and implemented across all the project team members involved in the clinical trials process.    The goal could be in the form of key success criteria. This aids an organization in stressing the path to its mission’s fulfilment. These performance-based indicators provide a metric for determining whether or not the organization is meeting its goals. 
  3. Developing Scale to Track Critical Success Factor – Scales and measurements keep track of progress once important success criteria are defined. This can be accomplished using a data reporting technique that collects specified information. Leaders should be informed of the information that has been processed. The purpose of the method is to improve the customer satisfaction index score. There must be a goal and a metric for determining whether or not that objective has been met. 
  4. Defining Defects for Each Process – Non-conformances occur as a result of a flaw in the product or a flaw in the process. It is necessary to measure and repair any problem that occurs. This can be done by determining what has to be done to fix the problem.
  5. Documenting and Keeping Records – QMS includes keeping record of information in the form of documents. The golden tip is to start from a less hefty documentation and move onto the more important ones. 
  6. Defining the Process Quality – Internal audits, management reviews, corrective and preventive action processes, and communication channels are all part of your quality assurance approach. 
  7. Understanding the Trainings to be Included – Everyone must demonstrate competence in the job. Training is simply the beginning and can take place on the job, in a classroom, or virtually. Internal auditor competency and CAPA training are two significant training areas. 
  8. Using the QMS – Using the QMS ensures that the highest quality product is produced. The procedure entails gathering non-conformances and their records, auditing data in accordance with the corrective and prevention plan and reviewing data in accordance with the Failure Mode Effective Analysis (FMEA) to be prepared for any concerns.
  9. Measuring, Monitoring and Implementation of Plans to Improve Output – Using a quality management system entails gathering data and analyzing it to see if it is fit for purpose and can produce the desired results. You will have to keep track of objectives and define new metrics for performance. You must have a keen eye for details by recognizing trends, patterns, and correlation. After identifying trends, you and your team must prepare for arranging new objectives, plan prospects that will help you reach these new goals and must keep the mindset of “maintaining the quality”.  

 Key Takeaway 

In order to provide quality data and a clinical trial that is inspection-ready, a clinical QMS must be implemented. By doing so, you will be able to obtain and retain accreditation, which will be necessary both locally and internationally. 

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.