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6 Steps to Creating SOPs for Quality and Compliance

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SOPs are crucial for ensuring compliance and conducting clinical trials. SOPs provide a standardized approach to clinical research processes, which is essential for maintaining consistency and quality across all study sites and participants. The lack of SOPs may result in several issues, such as inconsistent practices that result in disparities in data collection, analysis, and reporting, which may weaken the accuracy and dependability of the study outcomes.

Adhering to ethical and regulatory requirements in a research study can be challenging. Failure to follow standard operating procedures (SOPs) in clinical research can result in reduced efficiency and waste of time and resources in trying to determine the optimal way to perform tasks.

Why SOPs are Important for Clinical Research?

SOPs are important to clinical research as they provide:

  1. Detailed guidelines for the implementation of GCP principles which ensure that clinical trials are conducted in conformity with the ethical considerations and scientific quality standards.
  2. A standardized and streamlined approach to study procedures reducing variability of study tasks while also increasing inspection readiness strategies.
  3. Increased assurance of the safety and well-being of study participants as alignment of procedures and ethical practices and are in place.

Steps to Creating Effective SOPs

Creating effective SOPs can be challenging, but a well-designed and executed SOP can save time and resources, improve the quality of research, and reduce the risk of errors.

1.     Establish the SOP development team

The first step in creating effective SOPs for clinical research is to establish an SOP development team. The team should consist of individuals with relevant expertise and experience, including clinical research professionals, study coordinators, regulatory experts, and other stakeholders. The team should be responsible for overseeing the development and implementation of the SOPs.

2.     Identify the process

The next step is to identify the process for which the SOP is being developed. It is important to clearly define the process and the scope of the SOP. The process should be well understood by the team, and it should be clearly defined in the SOP to avoid any confusion or misinterpretation.

3.     Conduct a process mapping exercise

A process mapping exercise is a useful tool for developing SOPs for clinical research. It involves visually mapping out the process and identifying the key steps, inputs, and outputs. This exercise helps to identify areas where the process can be streamlined or improved, and it ensures that all steps are accounted for in the SOP.

4.     Develop the SOP

The next step is to develop the SOP. The SOP should be written in a clear and concise manner, using simple language. The SOP should include the purpose of the process, the step-by-step instructions for executing the process, the roles and responsibilities of team members, and any relevant references or supporting documents. The SOP should also include a section for deviations and corrective actions.

5.     Review and approve

Once the SOP has been developed, it should be reviewed and approved by the appropriate stakeholders. This includes the SOP development team, the study sponsor, the regulatory authority, and any other relevant parties. Feedback should be incorporated into the SOP, and revisions should be made as necessary.

6.     Train and implement

Training and implementation of the SOP should be conducted by the SOP development team. The team should ensure that all relevant personnel are trained on the SOP, and that the SOP is implemented consistently and effectively. The team should also monitor the implementation of the SOP and make any necessary updates or revisions.

Conclusion

In conclusion, creating effective SOPs for clinical research is critical for ensuring regulatory compliance, data integrity, and risk management. By following these six steps, the development team can create an effective and efficient SOP that will benefit the research team and the quality of the research.

 

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.

    Pharmacovigilance and Drug Safety

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    Recently approved medications and those already on the market can benefit from pharmacovigilance to help ensure patient safety. While pharmacovigilance practices are highly regulated in the context of clinical trials, post-marketing incidence reporting is not properly adopted or enforced. As a result, it is anticipated that adverse events related to medications that are already in the market are underreported by about 90%. Therefore, it can be difficult to identify drug safety problems in individuals who have numerous comorbid conditions and complex disorders.

    What is Pharmacovigilance?

    The research and practices involved in the identification, evaluation, comprehension, and avoidance of side effects or any other issue involving medications is known as pharmacovigilance.

    Before a treatment is approved for use, the only available proof of its efficacy and safety comes from clinical trials, in which patients are carefully chosen and monitored under carefully controlled settings. This indicates that a treatment has only undergone brief testing in a very small number of carefully chosen patients at the time of its authorization.

    Following approval, the medication may be administered to a large number of patients, continuously, and in conjunction with other medications. In such cases, some adverse effects could manifest. Therefore, it is crucial to continuously assess the safety of all medications used in medical procedures.

    How is Drug Safety Ensured?

    For the evaluation of prescription medications, there are regulatory frameworks. First, the FDA examines the efficacy and safety of new pharmaceuticals that manufacturers want to market in the United States during the premarket approval process. The FDA’s examination of the studies in which people use the investigational new medicine in meticulously controlled, typically randomized trials such as Phase 1, 2 and 3 trials.

    Second, the FDA takes action through its post market regulatory processes once a maker has sufficiently shown a drug or device safety and effectiveness for a specific population and set of conditions. Clinicians and patients may also report any significant or unusual adverse effects to the FDA.

    According to the law, the FDA is authorized to take only limited action if it determines that a product’s post-approval use entails a higher risk of a negative outcome. However, many argue that in addition to needing a wider variety of enforcement measures, FDA also has to make better use of the authority it already possesses.

    Six areas are discussed, including the FDA budget, the industry’s role, the opportunity to leverage the drug approval process to improve post market operations, the paucity of post-market data, and the limited public access to data obtained. The FDA is able to execute some of the recommended adjustments. Others would necessitate legislative action.

    Conclusion

    It is important to understand that no medication is 100% risk-free. A prescription drug is actually one that has “toxicity or other potentiality for harmful effect, or the method of its use, or the collateral measures necessary to its use, is not safe for use except under the supervision of a practitioner licensed by law to administer such drug,” according to the Federal Food, Drug, and Cosmetic Act.

    Therefore, it is important to ensure that the drug safety plan is working in all areas of the healthcare sector to ensure utmost safety. Regulatory authorities and pharmaceutical medicine pupils must adhere to the fundamental principle and primary objective of pharmacovigilance.


    References

    Jones, R. (2022, April 16). Pharmacovigilance – a complete guide to Pharmacovigilance and Drug Safety – Clinical Research Certification. CCRPS Clinical Research Taininrg. Retrieved September 24, 2022, from https://ccrps.org/clinical-research-blog/pharmacovigilance-training

    The theory and definitions of drug safety — pharmacovigilance. (2019). Cobert’s Manual of Drug Safety and Pharmacovigilance, 1–7. https://doi.org/10.1142/9789813278851_0001

    Yehia, D. H. (2022, June 24). Introduction to pharmacovigilance: How drug safety is enforced by pharmacovigilance – pharmacovigilance foundations. Pharmacovigilance Foundations – Simplifying Healthcare Professionals Workspace. Retrieved September 24, 2022, from https://www.pharmacovigilancefoundations.com/pharmacovigilance-introduction/

    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

    The Importance of Documenting and Reporting Adverse Events

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    One of the primary goals of every clinical trial is to evaluate an intervention’s safety and effectiveness to that of a control or other care. As a result, all studies expose participants to risk, and these are risks that may be similar to those they encounter in ordinary clinical practice in many circumstances. It is critical to document instances of injury or poor outcomes that occur during the study to ensure that both expected and unforeseen hazards are identified.

    Several phrases are frequently misconstrued as synonyms, including adverse events, adverse drug reactions, adverse effects, serious adverse events, serious adverse effects, side-effects, complications, and damages. When it comes to drug safety, though, both terms are often used interchangeably.

    The following are examples of adverse events (AEs):

    • A physiological occurrence, such as a rash.
    • A psychological occurrence, such as altered cognition.
    • An abnormality in the laboratory, such as a high creatinine level.
    • Increased severity of a pre-existing ailment, such as uncontrolled blood glucose levels

    Documenting and reporting adverse events; especially those events related to the study intervention helps in:

    1. Informing health authorities, clinical investigators, and others of new and important information about events that occur on a clinical trial
    2. Contributing to the summary of adverse experiences related to the development the drug, device or regimen toxicity profile

    Documenting Adverse Events

    All adverse occurrences must be recorded in the medical record of the patient. The study team must first grasp how AEs should be collected before documenting them. To avoid bias in AE collection, patients should not be questioned about specific occurrences that may be expected while on the trial.

    AEs should be reported or elicited from a person at each study visit in the following situations:

    • during open-ended inquiries
    • during examinations
    • during evaluations

    The collection of AE data begins when the study intervention (drug/procedure) is started. The AE data should be collected from the commencement of a placebo lead-in period or other observational period intended to establish the patient’s baseline status. The AEs should be observed until they resolve or stabilize. All AEs that necessitate interruption or termination of the study drug, or those that are present at the end of study treatment, must be followed up on.

    Reporting Adverse Events

    Clinical trials can be conducted in a single or multi-center setting. Multicenter studies include a larger number and a wider range of research participants, making it more difficult to track adverse events, and certain incomplete safety reports from these multi centers may reduce the overall understanding of the adverse event.

    The regulatory authorities must be able to analyze the safety information based on accurate documentation. The severity, study intervention relationship, action taken about the study intervention, adverse event outcomes, and if it was serious should all be documented.

    All observed adverse events, as well as all adverse events reported by study participants, must be documented by the investigator. Regardless of the seriousness of the information presented, it should be recorded and reported. This data is saved in the safety database for the medicine or device under evaluation.

    Conclusion

    Each adverse event must be understood, as well as its relevance and significance to the drug or device being tested. Patient safety is increased as a result of the recording and reporting of these incidents.

    Need inspection readiness assistance in your safety department or specialized training in the area of adverse events? Contact us! We’d love to hear from you to discuss strategies!

     

    References

    ClinicalTrails.gov. ClinicalTrials.gov. (n.d.). Retrieved June 11, 2022, from https://clinicaltrials.gov/ct2/help/adverse_events_desc#:~:text=Adverse%20Events%20are%20unfavorable%20changes,specified%20period%20following%20the%20trial.

    MB;, G. R. E. D. N. A. L. (2014). Registries for evaluating patient outcomes: A user’s guide [internet]. National Center for Biotechnology Information. Retrieved June 11, 2022, from https://pubmed.ncbi.nlm.nih.gov/24945055/

    What are ‘adverse events’ and why is it necessary to record and report them? students 4 best evidence tutorials and fundamentals. Students 4 Best Evidence. (2021, March 26). Retrieved June 11, 2022, from https://s4be.cochrane.org/blog/2021/03/26/what-are-adverse-events-and-why-is-it-necessary-to-record-and-report-them/

     

    3 Ways to Close the Diversity Gap in Clinical Trials

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    The selection of the appropriate research participants is critical to the success of any clinical trial. Regrettably, the majority of clinical trials done are severely lacking in diversity. All too frequently, cultural and genetic factors unique to Asians, African-Americans, Latino-Americans, and other ethnic communities can contribute to differences in treatment responses and risks of adverse events.

    Inadequate clinical trial representations of all populations can therefore leave underrepresented groups vulnerable due to the lack of subgroup-specific data. This disparity in diversity can lead to poor drug development and increase minority health inequities; however, there are ways to close this diversity gap.

    Three Ways to Close the Diversity Gap

    1. Educate Staff About Importance of Diversity in Trials

    The importance of diversity in clinical trials guarantees that they are being conducted properly and strategically. It’s important to learn more about the significant unmet needs of patients who could benefit from a therapy or medicine. If we know, for example, that a health problem would affect a diverse patient community in terms of “race” and ethnicity, we should plan ahead of time to ensure that those patients are equally included in the recruiting and selection process.

    2. Build Partnerships

    Engaging patients is a mission in which we are not only collaborating with various groups, advocacy organizations, and patients, but also building a method in which patients feel like they are a part of our scientific study from start to finish. A clinical researcher’s job entails analyzing real-world and secondary data  to better understand disease and treatment trends, track patients’ healthcare journeys, and find strategies to demonstrate its worth in improving health outcomes. The idea is to have a varied group of people at the table in order to come up with solid and relevant solutions.

    You learn to value patient, advocate, and expert collaboration. You will learn how to form relationships and engage in discourse from a variety of viewpoints. So that when it comes to performing research at various stages of the drug development process, you already have those partnerships in place and can use them to improve your knowledge and influence.

    3. Start at a Micro-Level

    Using more community-based routes that are congruent with how people may be familiar with acquiring information, such as barber shops, beauty parlors, or community centers, to contact and deliver information to possible study volunteers is an important tactic. Non-traditional outreach tactics not only help create valued relationships, it also provides essential information about the concerns of the community as it relates to participation in clinical trials.  Many in the community have difficulty participating in trials because of the historic and unethical Tuskegee Syphilis Study so of course, building trust in these communities is an important factor as well.

    Conclusion

    Minority involvement in clinical trials should be a primary focus for the entire health-care system. Participating in the aforementioned measures will help us develop medications more effectively, reduce minority health disparities, and improve overall public health. However, in order to reduce the diversity gap, more businesses and government agencies must support programs like these and be more empathic to the concerns of the minority communities.

     

    References

    Barron, D. (2015). Bridging the diversity gap in clinical trials: Reuters events: Pharma. Bridging the Diversity Gap in Clinical Trials | Reuters Events | Pharma. Retrieved May 23, 2022, from https://www.reutersevents.com/pharma/clinical/bridging-diversity-gap-clinical-trials

    Bodicoat, D. H., Routen, A. C., Willis, A., Ekezie, W., Gillies, C., Lawson, C., Yates, T., Zaccardi, F., Davies, M. J., & Khunti, K. (2021). Promoting inclusion in clinical trials—a rapid review of the literature and Recommendations for action. Trials, 22(1). https://doi.org/10.1186/s13063-021-05849-7

    Buckman, P. (2022, May 11). Council post: Bridging the gap: Why clinical trials have a diversity problem and how to fix it. Forbes. Retrieved May 23, 2022, from https://www.forbes.com/sites/forbesbusinessdevelopmentcouncil/2022/05/10/bridging-the-gap-why-clinical-trials-have-a-diversity-problem-and-how-to-fix-it/?sh=2b074b4a5078

    Janssen Oncology. (2021, December 16). Working together to close the diversity gap in clinical trials: Industry and researcher perspectives. STAT. Retrieved May 23, 2022, from https://www.statnews.com/sponsor/2021/12/06/working-together-to-close-the-diversity-gap-in-clinical-trials-industry-and-researcher-perspectives/

    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].

    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].

    Strategies Needed to Maintain Compliance in Clinical Research

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    “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!

    MY EXPERIENCE AS AN FDA INVESTIGATOR

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    I have been asked so many questions about my FDA career and what it was like working with the FDA.  I thought it would be best to write about my experience in an interview-based article according to the most frequently asked questions.

     How were you introduced to the FDA?

    I was introduced to the FDA in my last year of college at Rutgers University.  As I was prepared for graduation and entering the workforce, I also attended as many job fairs as possible. I thought that submitting my resume to as many companies possible would increase my chances of getting hired after graduation.  Of all the numerous job fairs I attended, FDA was only present at one of them.   I met the FDA representative, who was also the District Director, had a great conversation with her and handed her my resume which was added to the stack of resumes from hundreds of other candidates.

    How did you get hired to work for the FDA?

    Getting hired to work for the FDA was not easy.  After graduation, I was determined to have a career relative to biology or similar scientific field and the FDA was one of top companies I wanted to work for.  I was very persistent in having my name and resume stand out from the others.  For months, I called the District Director every other day to check in and see if she reviewed my resume.   My persistence paid off.  A couple of months later, I finally received a call from the district office to come in for a face-to-face interview.

    What was the hiring process like?

    The hiring process was pretty rigorous.  The interview was a few hours long.  It included an overview of FDA and discussion about me and my experience (although very limited as a college grad). It also included a long list of case-based scenarios along with questions on how I would handle each case.  The purpose of these questions was to test my moral character, sound judgement and ability to protect confidential information. 

    After being considered a potential candidate, I moved on to the next phase where there was the typical drug test, credit check and a detailed background check.  The background check not only included a criminal history check but a thorough investigation on me as person.  Not only were my past and current employers contacted and visited, but all of my neighbors from my current and past addresses as well!  

    What was a typical day in the life of an FDA Investigator?

    A day in the life of an FDA Investigator primarily involves preparing for and conducting inspections according to your specialty (Pharmaceuticals, Devices, Foods, Biologics).

    Inspections can be as short as a few hours or as long as a few weeks depending on the size of the firm and complexity of the inspection.  Other tasks include handling and investigating customer complaints and recalls in addition to attending meetings and continuous training sessions. Overall, the job entails a lot of travel, but the majority of it is local. 

    What’s the difference between FDA investigator and Inspector?

    FDA Investigators (or Consumer Safety Officer -CSOs) differs from FDA Inspectors (or Consumer Safety Inspectors- CSI) in that Investigator positions requires a Bachelor of Science (BS) degree (usually in science or engineering) whereas the CSI position does not.

    In addition, the role and responsibilities of an Investigator and Inspector are different.  Investigators are responsible for conducting domestic & international inspections and investigations in the areas of food/imports, pharmaceutical, biologic, BIMO and medical device; whereas Inspectors are responsible for performing import work which includes physically inspecting imported products in the aforementioned areas.   GCP/BIMO inspections, will always be conducted by an FDA Investigator.

    Why did you leave the FDA?

    Leaving the FDA and my colleagues was bittersweet.  I enjoyed working at the FDA but compensation was low (GS-5 which is $25K a year) as is expected for a government position.  At the time, there were so many opportunities in the industry looking for someone with my experience paying 2-3x as much, I could not say no.  I was curious to see what the industry had to offer.

    Any regrets leaving the FDA?

    Initially, I had regrets and wanted to kick myself for leaving, but as I started working in the industry and gaining more experience with CROs, pharmaceutical and medical device companies, my regrets started to dissipate.  I realized how valuable it was to work on “the other side” as it only diversified and enhanced my knowledge and experience.  If anything, continuing to work with the FDA would have limited me from seeing and understanding both perspectives.  Having the experience of seeing both sides (industry vs FDA) is truly priceless.

    Have more questions? Feel free to contact me at info@2kclinicalconsulting.com

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

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    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

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    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

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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.

     

    Understanding the CAPA Process

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    A corrective and preventive action (CAPA) plan is a set of steps done to address a compliance problem and, more significantly, to keep it from happening again. The immediate noncompliance and the broader nature of the problem will be the subject of a CAPA plan. It entails investigating the root cause and comprehending the problem, finding a solution, and ultimately avoiding recurrence. CAPA systems are important in clinical trials as it can be used to

    1. Address audit or inspection findings,
    2. Improve compliance and
    3. Reduce risk.

    Importance of CAPA System in Clinical Trial Settings

    During the clinical trial process, compliance to the GCP quality standard ensures that the information and drawn conclusions are credible and correct, as well as that the trial subjects’ rights, integrity, and confidentiality are safeguarded. The CAPA system ensures that the aforementioned conditions are met.

    But how can we ensure that we are following the right steps? Read ahead about the phases of the CAPA system.

    Phases in Implementation of the CAPA System

    Before you start a clinical trial, keep in mind the following phases to implement a successful CAPA system.

    1. CAPA Initiation and Problem Identification: To begin the CAPA process, the problem identification and commencement phase needs recording the issue. The description should include who, what, when, where, why, and how many people were involved. A detailed report is favorable.
    2. Risk Analysis: A risk analysis should be conducted based on the risk to the patient, user, business, and compliance. CAPA deadlines should be determined by the outcomes of the risk analysis. Low-risk problems, obviously, will not have the same sense of urgency as high-risk problems.
    3. Correction: To prevent additional deviations or discrepancies, correction  should be undertaken as early as possible. To identify if there are any systemic difficulties, the organization should examine linked processes and products.
    4. Root Cause Analysis & Investigation: The following are some of the most commonly used tools/methods for conducting investigations to find the underlying cause of a problem;
      1. Flowcharting
      2. Brainstorming
      3. Affinity diagrams
      4. Fishbone diagrams
    5. Corrective or Preventive Actions: Corrective and preventative activities are long-term strategies for resolving or eliminating the cause of a nonconformity or a possible nonconformity.
    6. Implementation: Corrective and preventative actions are initiated and implemented during the implementation phase to address the root cause or causes of a nonconformity. Procedural upgrades, training, and process improvements are just a few examples.
    7. Verification of Implementation or VOI: VOIs are used to ensure that promised and planned corrections, containment, corrective actions, and preventive actions were carried out.
    8. Verification of Effectiveness Plan (VOEP): The effectiveness plan phase establishes and defines preset criteria for determining whether corrective and/or preventive activities were successful.
    9. Verification of Effectiveness (VOE): The verification of effectiveness phase entails analysing and recording the VOE plan’s stated criteria. A successful effectiveness verification should show that the genuine root cause of the problem was correctly identified and that the remedial and/or preventive actions were helpful.
    10. Closure: This is the final step in the CAPA procedure. Only once the verification of efficacy has been satisfactorily performed should a CAPA be closed. If a CAPA is discovered to be unsuccessful, it is recommended starting a new one while referencing the old one.

    Conclusion

    CAPAs are required by regulations, standards, and guidelines by health authorities across the globe.  Having a CAPA system in place assists a clinical trial by strengthening its market advantage, reducing unnecessary costs and improving processes if completed appropriately. To ensure that the process phases are clearly defined, each phase of a CAPA should be its own part on a form as an electronic workflow.

    Struggling with creating effective CAPAs for your site or department?  Contact us! We’d love to hear from you to discuss strategies!

    All About Protocol Deviations

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    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!

     

     

     

     

     

    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. 

    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

     

     

     

     

     

     

     

     

    3 Surefire Ways your TMF can extend your Inspection

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    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

    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!  

    Determining Relevant Correspondence in the TMF

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    Correspondence in the Trial Master File (TMF) is imperative to keep all parties abreast of the details involved. In order to keep all information relevant and the entire TMF streamlined and efficient, it is necessary to decide what is important, applicable, and mandatory.

    Current health authority regulations require that organizations retain relevant correspondence.  This includes correspondence that is essential for reconstruction of activities, decisions in clinical trials and other important information. Other correspondence, like irrelevant correspondence, should be evaluated through a formal process to decide on whether it adds value or contributes to the story of the trial.

    Correspondence through email is a common and necessary way to convey information pertaining to the clinical trial; however, they can quickly overwhelm the entire process and create informational chaos when it comes to filing.  While emails are the quickest way to communicate to sites about trial updates, it is crucial to be able to determine the relevancy for a more streamlined filing process.

     Determining Relevance

    There are factors that can help you determine relevant correspondence to file in the Trial Master File. Individual organizations can expand on these criteria to clarify the terms within their own context and define their individualized filing approach in their Trial Master Plan.

    They can choose to file correspondence either:

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

    The following are considered relevant correspondence for the TMF:

    • Agreements – Any communication of agreements made between two or more parties or individuals pertinent to the study.
    • Relevant and significant discussions – Any discussion relating to changes made should be recorded and filed.
    • Protocol violations – All information regarding violations of the existing protocols set in place for the research must be tracked and filed.
    • Trial conduct – Information regarding the conduct of actions relevant to the clinical research is to be recorded and filed. For example, if the subject is eligible, and allowance of rescreening.
    • Adverse event reporting – All occurrences of serious issues associated with the clinical research should be filed.

    The Responsibility of Filing

    Once it is determined that an email or article is deemed important, the responsibility of whom should file it comes into play.  To avoid duplication of information or deletion of relevant details, it is important to lay out clear instructions so that everyone is on the same page. Therefore, drafting concise guides with best practices that are laid out clearly and assigning these tasks to the most efficient members of the team becomes paramount.

    Conclusion

    Often in a clinical trial, circumstances can change quickly. This requires the study team to adjust their trial conduct accordingly. Circumstances, such as the COVID-19 pandemic, forced teams to communicate more via email and other online technologies. With inboxes being inundated with reams of information, it is more imperative to have a streamlined filing process, especially when it comes to TMF correspondence.

     

    Planning for TMF Success

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    Tackling the Trial Master File (TMF) can seem daunting at times. With so many moving parts and documents, it can get more difficult to manage as a clinical trial continually progresses. However, the TMF is essential as it tells inspectors the story of a study from beginning to end.  

    Keeping the TMF up-to-date is crucial due to this very fact, but teams often struggle with getting it audit-ready due to disorganization and inconsistencies. Common challenges with TMFs (paper and electronic) are: 

    • Storing documents in several locations, making them difficult to access during an inspection.  
    • Limited collaboration between sponsors and CROs especially if there are different filing processes, systems, or incompatible software.  
    • Metrics can help provide key insight into organizational performance measures but  are also another source of frustration in TMF management because of the need to be updated regularly  

    These challenges can be addressed with setting up a plan, specifically, a TMF plan which could help streamline processes.  

    What is a TMF Plan? 

    The TMF Plan details every aspect of TMF management. It sets boundaries and specifies who is responsible for specific TMF sections. It could contain a TMF Master List or TMF Table of Contents (TOC) that outlines procedures such as deadlines for each document, study reports, or specific milestones unique to each organization.  

    The TMF Master List could also reference the Standard Operating Procedures, which describes each TMF document. Other types of information you might expect to see in this plan include TMF review frequency.  

    What is the purpose of the TMF Plan? 

    Transparency is key to building a high-quality TMF. The TMF Plan provides all information, data, and processes relevant to TMF management. This results in a complete TMF come inspection time and sets expectations for all parties involved. It is meant to keep sponsors, CROs, vendors, and other TMF stakeholders in the loop on everything from how documents are filed to the location of the TMF.  

    What is the format of the TMF Plan? 

    Having a TMF Plan is not required, but it helps keep everyone on the same page. It is especially important if the sponsor and CRO are both adding content and maintaining the TMF. Each organization will have its own approach as to how TMF management will work, and it generally helps to have TMF Plans that address the following TMF points:  

    • Official location 
    • Management procedure documents 
    • Breakdown of tasks & responsibilities 
    • Content filing processes 
    • Training and access management 
    • Structure  
    • How to add content  
    • TMF activity documents  
    • Formal archive plan 

    The above will largely vary based on your organization’s needs, but it is a solid starting point in formulating your new TMF plan.  

    Conclusion 

    Some of the biggest obstacles in a clinical trial are putting together an audit-ready TMF and having the metrics to back it up. You can avoid any of the unnecessary stress of inspections by having everything laid out from the start.  

    Having a TMF Plan in place gives your team and other stakeholders a micro and macro view of the TMF management process, from content procedures to specific deadlines when TMF deliverables are due. As a result, the TMF plan keeps everyone on track throughout the clinical trial and sets everyone on the right path for future successful inspections.  

    TMF Building Blocks to Inspection Readiness Success

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

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

    How should you organize the Trial Master File?

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

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

    How do you manage the Trial Master File?

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

    • Training

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

    • Clear Expectations

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

    • Self-Checks

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

    • Bottom-line: Document Everything

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

    Conclusion

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

    Inspection Preparation Concepts for Clinical Research Sites

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

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

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

    What to expect

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

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

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

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

    What to keep in mind

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

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

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

    Key Takeaway

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

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

     

     

     

    Location Matters…

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    What’s wrong with this picture?

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

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

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

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

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

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

    FACILITY AND STAFF PREPARATION

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

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

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

    INSPECTION ROOM VS SUPPORT/WAR ROOM

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

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

    KEY TAKEAWAY

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

     

    How To Implement Lessons Learned From Regulatory Inspections

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

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

    Implementing the lessons learned from regulatory inspections 

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

    1.Identify Lessons Learned 

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

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

    Ask the following questions: 

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

    2. Document Lessons Learned 

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

    3.  Analyze Lessons Learned 

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

    4.  Archive Lessons Learned 

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

    5.  Retrieve lessons learned 

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

    Takeaway message  

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

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