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Sponsors are responsible for monitoring studies, patient safety, and data integrity.
The International Conference on Harmonization Good Clinical Practice (ICH-GCP) indicates that it is the sponsor's obligation to monitor clinical research studies, ensuring patient safety and data integrity. This article will discuss the implementation of an objective internal monitoring program developed in a pediatric academic setting to provide continuous self-monitoring and assessment. This program assists in the overall process of monitoring, benefits investigator-initiated trials, and complies with Health Canada and FDA requirements. Additional benefits are quality improvement initiatives and the identification of deficiencies.
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Guidance on clinical trial design and execution has been established to ensure the reproducibility of study results and participant safety. ICH-GCP Section 5.18 states:1
The sponsor should ensure that the trials are adequately monitored. The sponsor should determine the appropriate extent and nature of monitoring. The determination of the extent and nature of monitoring should be based on considerations such as the objective, purpose, design, complexity, blinding, size, and endpoints of the trial.
International government agencies, specifically Health Canada,2 the EU Directive,3 and the FDA,4 refer to ICH-GCP when outlining the need for monitoring clinical trials. Therefore, by putting into place an objective internal monitoring plan, compliance with such regulations is able to be maintained.
Regular, consistent monitoring of clinical trial activity also facilitates the identification of research program specific challenges through objective tallying and categorizing of findings.
In order for internal monitoring to act as an effective form of auditing, an objective approach must be applied. To ensure impartiality of the review it is essential to develop a standard operating procedure outlining the monitoring plan, expectations of the monitor, and a proposed action plan for findings. The elements outlined in Table 1 should be considered and documented within the process.
Table 1. Various elements should be considered and documented to ensure the impartiality of the reivew.
To ensure the objectivity of internal self monitoring, a monitoring template can be employed. After identifying the elements to be monitored, create a "yes/no" style checklist with the opportunity for comments. Developing a single monitoring checklist for all studies within the research enterprise results in a standard approach to reviewing all studies. The "yes/no" checklist provides an impartial approach to documenting the findings.
Collate all findings to recognize trends and potential issues. These issues are quickly identifiable as areas for quality improvement within the research enterprise. By further categorizing deficiencies into major and minor findings, time-sensitive and serious potential problems for careful prioritization and necessary action can be highlighted (Table 2).
Table 2. By categorizing deficiencies into major and minor findings, time-sensitive and serious potential problems can be highlighted.
The internal monitoring model is cyclical (Figure 1). Monitoring results in findings lead to quality improvement plans and education. Follow up through subsequent monitoring ensures the effectiveness of action plans and identifies potential new deficiencies.
Figure 1. Cyclical monitoring leads to quality improvement plans and education.
Accurate internal monitoring documentation shows compliance with regulations. Documentation should include the monitor's name, the date monitoring occurred, what was reviewed, deficiencies, names of those with whom the deficiencies were discussed, the subsequent action plan, and the follow up. The report should be maintained with other documents essential to the study as per regulation (i.e., 25 years as per Health Canada).
When recurrent issues or themes are identified they may speak to the need for the development of a specific policy, standard, or improved training program. Re-auditing areas of concern after implementation provides the ability to measure success.
A well-established dissemination plan is absolutely essential to ensuring that appropriate institutional staff members are made aware of problem areas. Findings should be discussed in a multi-disciplinary setting. Potential solutions are then the result of multi-disciplinary feedback that combines expertise in regulations of clinical research with the clinical management of patients. The themes that present themselves through this feedback are the critical issues to improve upon. A successful program highlights urgent issues and creates and implements viable solutions quickly and effectively (Table 3). When creating an action plan, clearly identify who will be responsible for each aspect and make sure that there is a point person who will continue to follow up to ensure that the plan is carried out. Be certain the action plan and follow up are well documented to show the noted issues were addressed. As the principal investigator is ultimately responsible for all research activity, they must be well informed and represented within the committee with all appropriate documentation.
Table 3. A successful program highlights urgent issues and creates and implements viable solutions.
Monitoring generally results in findings. For example, clinical research in pediatric cancer is conducted in the real life clinical setting, therefore there are few reviews that will not result in some deficiencies. An effective monitoring plan acts as the catalyst for change by identifying deficient areas within the research program. Internal monitoring measures institutional issues, validates concerns, and tracks improvement. Understanding the importance of sharing monitoring findings is imperative, regardless of the gravity of the issue. The research group must always be aware of the challenges so the next steps for resolving the issues may be established. All monitoring should result in findings—some minor, others major. Ensure that internal monitoring has a purpose by escalating concerns and outlining an effective action plan to work toward eliminating these gaps moving forward.
An objective monitoring plan results in adherence to ICH-GCP and thus national and international regulations governing clinical trials. An effective monitoring plan has a pre-defined approach and reaction to findings that includes quality improvement and education. It acts to continuously raise the bar of research excellence within a program. Internal monitoring allows a program to identify deficiencies, recognize opportunities for improvement, and measure their success.
Ashley Mehta,* Hons B.Sc., CCRP, is Team Leader, CTSU, e-mail: firstname.lastname@example.orgSusan Devine, CCRP, is Senior Manager, CTSU, both at The Hospital for Sick Children, Division of Haematology/Oncology, 555 University Ave, Toronto, Canada.
*To whom all correspondence should be addressed.
1. International Conference On Harmonization, "ICH Harmonized Tripartite Guideline: Guideline for Good Clinical Practice," (1997), http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6_R1/Step4/E6_R1__Guideline.pdf.
2. Health Canada, "Consolidated Statutes and Regulations, Food and Drug Act, Division 5 Drugs For Clinical Trials Involving Human Subjects," (2004).
3. "Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001 on the Approximation of the Laws, Regulations and Administrative Provisions of the Member States Relating to the Implementation of Good Clinical Practice in the Conduct of Clinical Trials on Medicinal Products for Human Use," Official Journal of the European Communities, L121, 34-44, (2001).
4. US Food and Drug Administration, "Protection of Human Subjects," Code of Federal Regulation, Title 21, (2004).