Review These Documents Explained for Students (Easy Guide)

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This topic involves review these documents. A strong answer should include explanation, application, and examples.

Original Question

Review these documents. An additional one can be used but is not required. Build a case for the use of the risk-based monitoring approach. The central monitoring plan and analysis report (attached) are in line with risk-based monitoring. They are used in a way to support this type of monitoring by reviewing the “highest risk” issues at sites. In this case, its evaluation of SAEs and AEs, query generation and solution timelines, and issue trending. Introduction and conclusion. Be thorough – consider what you are covering in the paper and highlight that in the intro. The intro must include a concise yet clear idea to the reader on what you plan to cover in the paper, which does include your general List at least two (3 is optimal) steps on how Risk-Based Monitoring (and therefore, central monitoring) is set up/functions. So you are “educating” your team on this approach. This way, there is a natural flow from the benefits of central monitoring to mitigating risks. Three (3) benefits of the risk-based monitoring approach/central monitor usage. Examples are recommended. Use liberties or use the central monitoring report and attachments as a means to find the right “benefits” to highlight. Two (2) robust ways to mitigate the risk with one example each (specific or general is fine) of a site trending negatively (for example: what would you as the monitor or monitor manager for the sites that may be showing higher “risk”); (hint: would you recommend a certain type of action? Check the textbook for ideas – remember ideas such as CAPA, additional monitoring, etc. You can take liberties here since you not have the “monitoring plan” for this study -that’s ok. Just think about what options may help). **Use examples!! The example report in this assignment can be used or some aspects can be highlighted/referenced. Consider this paper going to your internal clinical team members. Consider that you are sharing some insights you have gained on central monitoring from the reports you have (let’s say, for example, this is the first time you employed the central monitoring strategy on your clinical trial (CRO or sponsor) and you are now reporting on its success/ whether the team should use this same approach in the future. Change is hard for companies, so how would you relay the importance of what was gained from this approach? Examples help a lot). Identity two follow-ups from these two mitigations. For example, if you are setting up a CAPA, what follow-up may be needed for that CAPA? If you are setting up additional monitoring visits, what is going to be the potential trigger to stop the added monitoring visits? For example, how does this central monitoring approach/risk-based monitoring approach possibly HELP with risk follow-up (hint: often, it’s already built into the monitoring plan, so there is no additional thinking that has to be done on the spot. Instead, the risk and plans for risk is built in so all monitors may be able to be more consistent in their approach globally or across the study sites for the entire study)? *** Food for thought: how does RBM/CM potentially benefit an institution financially in the short term versus the long term? What is the evidence, thus far, on the benefits of RBM/CM? How might this impact the CRA/monitors on a trial short term/long term? How about the team itself in regards to the data they would have available at any given time? How would this impact the medical monitoring team (more “live” data for review)? not each have to be addressed, but I am giving you a leg up so you can focus on the critical aspects of this approach. Background Infrastructure and processes are necessary to protect the safety of their research subjects and ensure trial data integrity. In tandem, both the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) released draft guidance for the conduct of risk-based monitoring to assist sponsors in better meeting their regulatory obligations in 2011. While these guidelines provided the regulatory perspective and rationale for risk-based monitoring strategies, they did not mandate specific methodologies for implementation. Sponsors, who must implement risk-based monitoring solutions in such a way that meets the requirements, will be successful, and documented. As we are learning in this course, traditionally sponsors manage this aspect of the trials with different software systems and paper processes to oversee monitoring /reporting, safety and pharmacovigilance reporting, document tracking overall, Trial Master File maintenance; and electronic data capture and query management. Information is tracked within these separate systems and made available to users through disconnected, preprogrammed status reports. There is often a heavy reliance on manual tracking to analyze disparate data. Central monitoring and analytics software and expertise is starting to emerge especially through the TranCelerate “model”. This new platform seems to be accelerating the gathering and understanding of clinical trial data. Sponsors and their global project teams need a comprehensive and compliant solution, one that allows trial oversight through real-time proactive risk assessment. Key here is the idea of the “availability of real-time, continuously analyzed data and configured workflows greatly reduces, or even eliminates, the potential for individual bias in issue management and decision-making.” Disproportionately high level of monitoring oversight can be expended for relatively low-risk situations. The FDA believes that targeted risk-based approaches that focus on the most critical data elements will result in more effective monitoring and help to overcome many of the limitations of on-site monitoring. Draft Guidance on Risk-based Monitoring The European Medicines Agency (EMA) The EMA suggests that sponsors take a quantitative approach to the issue and assign numeric values to specific risks identified in the protocol (both high and low risks showing a range of “acceptable tolerance”. See analytics for more details). When acceptable tolerance limits are passed, the assigned escalation previously detailed in the study planning is triggered (for example, depending on the nature of the issue, this could trigger a phon call from the on-site monitor or an additional visit by the onsite monitor). However, if a deviation falls within the set tolerance range, then it may be considered an “expected deviation” per the monitoring plan for the protocol. The EMA states that tolerances/range limits should be defined early and documented in a monitoring plan clearly. For those variables that are important to the trial objectives, the plan could include more emphasis on central monitoring, quality assurance and targeted SDV. The EMA guidance exists within the framework of the Clinical Trials Directive and accommodates a range of risk-adapted approaches that will simplify clinical trial processes. Food and Drug Administration Perspective (FDA) The FDA draft guidance shares many of the central tenets of the EMA’s reflection paper, including the requirement for sponsors to use a variety of approaches to fulfill their responsibilities related to monitoring; investigator conduct and the progress of investigational drug and device exemption studies; Conduct a risk assessment to identify and evaluate risks critical to studying data and processes; Design a monitoring plan tailored to address the important and likely risks identified during the risk assessment (including remote, targeted and reduced SDV). The guidance highlights the importance of documenting the monitoring plan afterassessing the project risks and needs. It also recommends that sponsors analyze ongoing data to continuously assess and adjust the monitoring strategy. This is a vastly different approach from the traditional method of prospectively planning monitoring visits at regulator intervals, regardless of therapeutic area, trial phase or trial complexity. Both the FDA and EMA encourage sponsors to adopt strategies that reflect a risk-based monitoring approach using a combination of monitoring strategies and activities. The approach should include a greater reliance on centralized monitoring, a sharp focus on critical study parameters (such as those specific to the safety and protection of human subjects) and a plan to address data integrity risks. Moving forward Industry sponsors must proactively plan risk-based monitoring while instituting guidance from the regulatory agencies and incorporate learnings from traditional methods of monitoring. Ultimately thinking of how they will utilize this approach and incorporate strategies that can actually oversee all data/systems used in the study. (this is the challenge). “Reflection Paper on Risk-Based Quality Management in Clinical Trials,” European Medicines Agency, Aug. 2011, “Guidance for Industry Oversight of Clinical Investigations: A Risk Based Approach to Monitoring (Draft Guidance),” U.S. Food & Drug Administration, August 2011, http://www.fda.gov/downloads/ Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM269919.pdf. “Risk-Adapted Approaches to the Management of Clinical Trials of Investigational Medicinal Products,” Medicines and Healthcare Products Regulatory Agency, Oct. 10, 2011. “Guidance for Industry Oversight of Clinical Investigations: A Risk Based Approach to Monitoring (Draft Guidance),” U.S. Food & Drug Administration, August 2011. “Monitoring the Quality of Conduct of Clinical Trials: A Survey of Current Practices,” Clinical Trials, Vol. 8, No. 3, pp 342-349, June 2011, Central Monitoring Plan Introduction The plan describes tasks performed by the Central Monitor and the approximate frequency of performance. In addition this guideline defines the minimum criteria for central monitoring and does not replace an understanding of, or adherence to, the requirements contained in the approved protocol and/or applicable procedures. Roles and Responsibilities This plan establishes the procedures that will be followed by the Central Monitor for the XXX study. The Central Monitor is responsible for review of data throughout the study to assess site performance and potential risk to the study. Central Monitor (CM) The CM will be responsible for consultation in the development and review of analytics used for the conduct of central monitoring. The CM will hold routine meetings with the CTM and will be responsible for communication of issues to site monitoring representatives. The CM will enter issues identified through the central monitoring into an issues tracking system. Site monitors will be notified of open issues and will take appropriate action to resolve these issues. These actions will be documented in the issues tracking system. The central monitor will remain blinded until unblinding is approved by appropriate study team personnel. Central Monitoring Tasks This section includes the tasks and reviews to be completed by the responsible party (as noted in the table below) to monitor the progress of the trial. As a result of completing these tasks, areas requiring further investigation may be identified. Any issues detected through the investigations should be communicated to the study team. Issue ID Category Sub-category Requirement Risk Indicator(s) Threshold Description of Task Approximate Frequency IP Investigational Product Investigational Product (IP) Confirm subject received IP. Subject(s) did not receive study treatment. 1 or more subject(s) with IP eCRF inconsistent with IP IWRS data (e.g., not recorded in eCRF, recorded in eCRF but not consistent with IP data) Review IP reports to confirm that all patients assigned to a treatment are accounted for in eDC data and that patients receiving treatment per eDC are listed on IP reports. CRF and IP data will be used to assess this requirement. Monthly Issue by Site Issues Management Issues and Deviation Management Review/control issues for the study – based on the predefined risk indicators and thresholds. Follow up with appropriate action as per issues management SOP. Late or lack of sufficient resolution of issues at a site or an excessive number of issues at a given site (significant or non-significant) in comparison to other sites. 1. A site with 100% more unresolved issues than the median number of unresolved issues at all sites. Identify sites with 100% more unresolved issues than the median number of unresolved issues at all sites. Monthly Issue & Dev Mgmt Issues Management Issues and Deviation Management Review/control issues for the study – based on the predefined risk indicators and thresholds. Follow up with appropriate action as per issues management SOP Late or lack of sufficient resolution of issues at a site or an excessive number of issues at a given site (significant or non-significant) in comparison to other sites. 2. A site with 1 or more issues that are unresolved greater than 60 days. (Analytic Name: Issues List) Identify sites with unresolved non-significant issues more than 60 days old (Analytic Name: Issues List). Monthly SAE Safety Serious Adverse Events (SAE) Perform data review of SAEs leading to discontinuation of treatment or discontinuation from the study Increased number of subjects with SAEs leading to discontinuation at a site. Identify sites with 2 or more subjects who suspended or discontinued study drug due to SAE. Identify sites with 2 or more subjects who suspended or discontinued study drug due to SAE. Monthly Nonserious AEs Safety Non-Serious Adverse Events (AE) Perform data review of AEs Inaccurate or under/over reporting of AEs. Identification of a site where the average number of AEs per subject is more than 2 SD higher than or more than 2 SD lower than the average number of AEs per subject across all sites. Identify sites where the average number of AEs per subject per site is greater than or less than 2 standard deviations (SD) from the average number of AEs per subject per site across all sites. CRF data will be used to assess this requirement. Monthly Av Query Response Time Data Quality Central Data Review Monitor CRF completion Persistent late entry of data into the eDC tool at a site. Failure of an investigator to sign CRFs in a timely manner. 1. Identification of a subject for whom the average time from visit date to entry of data into eDC for all visits exceeds 10 days. Identification of a subject for whom the average time from visit date to entry of data into eDC for all visits exceeds 10 days. Monthly Overdue data entry by Site Data Quality Central Data Review Monitor CRF completion Persistent late entry of data into the eDC tool at a site. Failure of an investigator to sign CRFs in a timely manner. 2. Identification of sites where subjects have discontinued or completed the study where the CRFs have not been signed off within 30 days. (Analytic Name: CRF sign-off). Identification of sites where subjects have discontinued or completed the study where the CRFs have not been signed off within 30 days. (Analytic Name: CRF sign-off). Monthly . Overdue queries by data point & site Data Quality Central Data Review Monitor CRF query management Late or inadequate resolution of queries. 2. Identification of a site with more than 5 overdue queries. Overdue is defined as more than 30 days elapsed from initial query without resolution. Identification of a site with more than 5 overdue queries. Overdue is defined as more than 30 days elapsed from initial query without resolution. Monthly Overdue queries by data point & site Data Quality Central Data Review Monitor CRF query management Late or inadequate resolution of queries. 3. Identification of a site where the average number of queries per completed field is more than 2 SD greater than the average number of queries per completed field across all sites. Identification of a site where the average number of queries per completed field is more than 2 SD greater than the average number of queries per completed field across all sites. Monthly Re-query Rate Data Quality Central Data Review Monitor CRF query management Late or inadequate resolution of queries. 5. Identification of a site whose average requery rate per subject is more than 2 SD greater than the average requery rate across all sites. Identification of a site whose average requery rate per subject is more than 2 SD greater than the average requery rate across all sites. Monthly Queries per Subject Visit Data Quality Central Data Review Monitor CRF query management Late or inadequate resolution of queries. 6. Identification of a site whose average number of queries per subject visit is more than 2 SD higher than the average number of queries per subject visit across all sites. Identification of a site whose average number of queries per subject visit is more than 2 SD higher than the average number of queries per subject visit across all sites. Monthly Overdue Queries by site Data Quality Central Data Review Monitor CRF query management Late or inadequate resolution of queries. 7. Identification of a site whose overdue queries (as a percent of all queries at that site) is more than 2 SD higher than the overdue query percentage across all sites. Identification of a site whose overdue queries (as a percent of all queries at that site) is more than 2 SD higher than the overdue query percentage across all sites. Monthly Not visualized in analytics Study Management Subject Recruitment Evaluate subject recruitment by site including subjects enrolled and screen failures An increase or decrease in the rate of subjects failing screening at a site or deviation from planned enrollment rate. 1. Identification of a site whose ratio of screen failures to enrolled subjects is greater than 2 SD of the ratio of screen failures to enrolled subjects across all sites. Identification of a site whose ratio of screen failures to enrolled subjects is greater than 2 SD of the ratio of screen failures to enrolled subjects across all sites. Monthly Not visualized in analytics Study Management Subject Recruitment Evaluate subject recruitment by site including subjects enrolled and screen failures An increase or decrease in the rate of subjects failing screening at a site or deviation from planned enrollment rate. 2. Identification of a site whose average number of enrolled subjects per month is less than 50% of expected average enrolled subjects per month (expected enrollment rate is 1 patient/site/month). Identification of a site whose average number of enrolled subjects per month is less than 50% of expected average enrolled subjects per month (expected enrollment rate is 1 patient/site/month). Monthly Not visualized in analytics Study Management Subject Recruitment Evaluate subject recruitment by site including subjects enrolled and screen failures An increase or decrease in the rate of subjects failing screening at a site or deviation from planned enrollment rate. 3. Identification of sites with a time from last subject enrolled greater than 60 days while enrollment is still ongoing. Identification of sites with a time from last subject enrolled greater than 60 days while enrollment is still ongoing. Monthly . Not visualized in analytics Study Management Subject Discontinuation Evaluate subject disposition by site including subject continuation, discontinuations from the study, discontinuations from study treatment, drop-outs, lost to follow-up, and completions. Increase in early discontinuations of study treatment at a site or an imbalance in the reasons for discontinuation at a site. 1. Identification of a site whose rate of early discontinuations (number of subjects discontinuing study treatment prior to completion of the expected course of treatment divided by the total number of subjects enrolled) is more than 2 SD higher than the rate of early discontinuations across all sites. Identification of a site whose rate of early discontinuations (number of subjects discontinuing study treatment prior to completion of the expected course of treatment divided by the total number of subjects enrolled) is more than 2 SD higher than the rate of early discontinuations across all sites. Monthly Not visualized in Analytics Study Management Subject Discontinuation Evaluate subject disposition by site including subject continuation, discontinuations from the study, discontinuations from study treatment, drop-outs, lost to follow-up, and completions Increase in early discontinuations of study treatment at a site or an imbalance in the reasons for discontinuation at a site. 2. Identifications of a site where the proportion of subjects discontinuing for a given reason is more than 2 SD of the proportion discontinuing for that reason across all sites. Review all reasons for discontinuation to identify any trends in discontinuations (review those discontinuations due to physician decision or subject decision reasons as compared to other sites). CRF data will be used to assess this requirement. Identifications of a site where the proportion of subjects discontinuing for a given reason is more than 2 SD of the proportion discontinuing for that reason across all sites. Monthly https://docs.google.com/spreadsheets/d/112GXG_2D2YBea9xPAJxZJ3W-UWJuibV-/edit?usp=sharing&ouid=100618765761167624455&rtpof=true&sd=true

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