2k Clinical Consulting, Inc.

Menu

Blog Articles

Strategies Needed to Maintain Compliance in Clinical Research

by

“We are constantly working towards the highest level of compliance possible.” – Mike Davidson

In clinical research, compliance is essential to ensuring that the research trial is conducted safely and accurately. The ability to maintain the highest level of compliance requires an organized and streamlined process throughout the trial.  If a clinical site or sponsor company is unable to maintain compliance, the site staff and trial team will continuously struggle to be inspection-ready throughout every phase of the trial from start-up to closeout.

This article will define compliance and discuss what three (3) strategies can be utilized to maintain compliance when conducting a clinical trial.

Compliance Defined

Compliance refers to the act of adhering to a set of regulations, processes, or rules without raising any objections or raising concerns. This process takes place during all stages of clinical research. Regulatory compliance is critical in clinical research since it helps to ensure that all research is done safely and appropriately.  Deviations from compliance and quality standards can quickly affect clinical sites and sponsor companies and ultimately, the integrity of the product and clinical data.

How to Maintain Compliance

Three strategies that can be utilized in maintaining compliance are:

  1. Internal audits – conducting regular internal audits and document reviews ensures adherence to the protocol requirements and study procedures such as the consenting process, visit schedules and source documentation. In addition, internal audits and document reviews address prompt reporting and resolution of issues such as protocol deviations, temperature excursions and safety-related issues. 
  2. Ongoing staff training– clinical staff and trial team members should receive continuous training throughout every phase of the trial(s) on how to maintain compliance with the protocol, trial procedures and applicable requirements from regulatory authorities.
  3. Automated processes – automating processes of creating, reviewing and approving quality and clinical trial documents such as Standard Operating Procedures (SOPs), protocol deviations, Case Report Forms (CRFs) and training records, reduces error and increases compliance amongst clinical staff and trial teams.

Conclusion

Maintaining compliance in clinical research is essential to ensuring that the trial is conducted safely and accurately. Maintaining compliance in clinical research may be achieved by conducting internal audits and document reviews, continually training staff and automating clinical trial process. Implementing these strategies are essential to achieving inspection readiness and being successful in the conduct of clinical trials overall.

Struggling to maintain compliance at your clinical staff or clinical department?  Contact us! We’d love to hear from you to discuss strategies!

Source Documentation: “May the SOURCE Be with You…”

by

Lack of consistent, clear, and adequate source documentation is one of the most typical inspection results in investigator site inspections. This is also the most discovered flaw during sponsor audits. To guarantee that the study results are established on the foundation of trustworthy and legitimate data, investigator sites must be reminded of the need for good documentation practices. 

The origins of excellent documentation standards can be found in the (International Conference of Harmonizaton – Good Clinical Practice) ICH-GCP, which defines source data and source documents. 

 ICH E6 1.51 source data 

This includes all original documents and authenticated copies of original records of clinical results, observations, or other activities in a clinical trial that are required for the trial’s restoration and assessment. The documents containing source data are referred to as sources. 

ICH E6 1.52 source documents 

This includes original documents, data, and records such as hospital records, clinical and office charts.  The ALCOA-C acronym (attributable, legible, contemporaneous, original, accurate and complete) was coined by the US Food and Drug Administration to describe key characteristics of acceptable documentation. The World Health Organization has also adopted these. These requirements have changed over time. More ‘letters’ have been added by the EMA to indicate features of good source documentation, particularly for computerized systems. 

 Common Findings Associated with Source Documentation 

Following are the common findings associated with source documentation: 

  1.  It was not possible to validate the eligibility criteria. 
  2. Because there were multiple entries for the same data point, it was impossible to tell which one was the correct source record. 
  3. Inconsistencies in records were used to corroborate the study’s primary effectiveness outcome. 
  4. Abnormal lab values were not indicated on lab reports nor any contradicting material gathered in source documentation have been shown clinical importance. 
  5. Missing pieces of information from subject interview scales, a slew of unexplained revisions months after the initial entries, and contradictory data; erroneous subject identification, inaccurate date were identified. 
  6. Factually inaccurate paperwork regarding drug disposition—dates, amount, and subject use were found.  

How Can Documentation Be Improved? 

Documentation can be improved by the following ways:

  • Give PI the responsibility to assign tasks to the trained staff. 
  • Commitment and continuous presence must be acknowledged by the Principal Investigator (PI) throughout the study. 
  • Sites conducting the study must prepare SOPs which ought to be shared with the Contract Research Organization (CRO) or study sponsor. 
  • All technical aspects must be clear of confusions and errors prior to starting work on any study.
  • The sponsor and/or the CRO ensure PI’s commitment to the study.  

 Conclusion 

The ALCOA-C and other properties indicated by regulatory agencies and GCP should be demonstrated in source documents. During regular audits, the most frequently stated findings are those linked to source documentation. The PI’s dedication to the trial and participation in it makes a tremendous difference. Efforts to educate sites, understand their practices from the pre-study visit onwards, and to monitor and train them on a regular basis will all aid in increasing and sustaining the quality of site source documentation procedures. 

 

References 

“ALCOA”: Elements of good documentation. (n.d.). Retrieved October 24, 2021, from https://blink.ucsd.edu/research/policies-compliance-ethics/compliance/ALCOA-Standards-210304.pdf. 

Bargaje, C. (2011, April). Good documentation practice in clinical research. Perspectives in clinical research. Retrieved October 24, 2021, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3121265/. 

Commissioner, O. of the. (n.d.). List – ich guidance documents. U.S. Food and Drug Administration. Retrieved October 24, 2021, from https://www.fda.gov/science-research/clinical-trials-and-human-subject-protection/ich-guidance-documents. 

GLP documentation. (2007). Good Laboratory Practice Regulations, 241–258. https://doi.org/10.3109/9780849375842-11  

 

 

FDA vs EMA in Terms of GCP Inspections

by

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

by

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.

 

All About Protocol Deviations

by

The protocol for a clinical trial describes the entire study in detail, including the operational details of how it should be carried out. The purpose of the study protocol is to protect the health and safety of study participants while also proving efficacy of the product; however, when tasks are done outside the protocol, deviations are required.

What is a Protocol Deviation?

A protocol deviation happens when the activities of a researcher deviate from the Institutional Review Board-approved protocol without having severe implications, such as missing a visit window because the participant is travelling. It’s not as bad as a protocol violation which is a deviation from protocol that materially:

  • Decreases the quality or integrity of the information,
  • Causes the Informed Consent Form to be erroneous, or
  • Has an impact on the safety, rights, or wellbeing of a participant.

How Protocol Deviations Fit in a QMS

Some examples of protocol deviations occurring are:

  • Enrolling ineligible subjects
  • Lack of re-consenting subjects after amended protocols
  • The consent is missing signatures from subjects.

When deviations occur, the handling and resolution is intertwined in the QMS to ensure inspection readiness.  The organization could have a brainstorming session to discuss the deviation’s potential causes and effects in addition to what steps will be taken to prevent or mitigate the risk. These mitigations can then be monitored and reviewed on a regular basis, with specified thresholds for when a problem with trial registration becomes a substantial problem.

Important vs Non-Important Deviations

Once a procedure deviation has been found, it can be classified as either important or not important. Important protocol deviations can be defined using risk-based methodologies from ICH E6 R2.

Important protocol deviations are defined as subsets of protocol deviations that have the potential to have a major influence on the completeness, correctness, or reliability of essential study data, as well as a subject’s rights, safety, or well-being. Important protocol deviations, for example, could include enrolling individuals who do not meet critical eligibility criteria or neglecting to collect data needed to interpret primary endpoints, both of which could jeopardize the trial’s academic validity.

The International Conference on Harmonization (ICH) does not have a clear definition of a non-important protocol variation. As a result, if a procedure deviation does not match the requirements for being vital, it is considered non-important. Important and minor protocol deviations are both gathered, processed, and reported, albeit the processes may differ.

Conclusion

The cornerstone of a well-executed clinical trial is a well-thought-out and thorough protocol. Attend all sponsor-related meetings linked with the clinical study as the lead investigator. If you have any questions about the protocol or any study-related documentation, you should ask them right away to avoid any problems later. Finally, review the study, visit schedule and make plans ahead of time to prevent deviations.  

Struggling with minimizing protocol deviations for your site or department?  We’d love to hear from you to discuss strategies!

 

 

 

 

 

Steps on Implementing a Clinical QMS

by

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. 

Key Aspects of an Inspection Ready TMF

by

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

 

 

 

 

 

 

 

 

3 Surefire Ways your TMF can extend your Inspection

by

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

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.