Associate Director, Clinical Quality Management, EMD Serono
Abstract: Sponsors and contract research organizations should be using electronic clinical trial management systems to efficiently oversee their trials. This article describes the basic structure of clinical trial management systems and the need for these systems. Benefits of using an integrated clinical trial management system are highlighted, including the ability to link to other systems, running reports, and outputs such as executive management reporting dashboards, listings, and merged datasets. Requirements for compliance with 21 CFR Part 11 are described.
Disclosure: The author is not writing this article on behalf of his employer.
Introduction to Electronic Clinical Trial Management Systems
In short, a clinical trial management system (CTMS) is:
“…a software system used by biotechnology and pharmaceutical industries to manage clinical trials in clinical research. The system maintains and manages planning, performing and reporting functions, along with participant contact information, tracking deadlines and milestones.” (Source: Wilkipedia: https://en.wikipedia.org/wiki/Clinical_trial_management_system)
A CTMS is essentially a one-stop shop where anybody in the organization can go to get all of the necessary information about a given clinical trial. CTMSs are very robust. Based on the organization’s needs, a CTMS can be simple or very comprehensive. Larger pharmaceutical and biotech companies have massive CTMSs, which take a great deal of work to maintain. The use of a CTMS, however, is very beneficial for both study staff and senior management.
Before CTMSs, pharmaceutical, biotechnology companies, and contract research organizations (CROs) had to maintain many listings and spreadsheets over the life of a clinical trial. There were multiple sources of data including the need of extensive data entry that led to duplicate places for data to be captured and no single source for information. During that time, there was extensive administrative work that was required to compile information across trials often slowing down the efficiency of a clinical trial. Companies had to staff numerous people to ensure that enough resources were in place so that the more senior trial leaders were not burdened by these activities. Once electronic systems started to enter the work place, CTMSs were one of the first types of systems used by pharmaceutical and biotechnology companies and CROs to try to consolidate the work involved in managing clinical trials. Prior to the formalization of more packaged CTMS systems, teams were creating homegrown databases that essentially were the start of the CTMS development.
The Business Need for CTMSs
CTMSs streamlined the work involved in managing clinical trials. All organizational data, tracking information, and reporting now can come from one central and reliable source. This reduces the amount of effort, time, and resources needed to manage a trial. As such, there has been a trend for pharmaceutical and biotechnology companies to reduce the amount of staff needed and ultimately create a leaner organization. If the CTMS is kept up to date as the study progresses, the system allows for timely reporting and timely data exports.
Since the linking of electronic systems has improved from the early 2000s, much less manual work is required in managing clinical trials. The use of CTMSs reduces the number of people needed for data entry, which also reduces the chance for human error. One of the major problems seen before CTMSs was a lack of consistency between data sources. This has been eliminated or significantly reduced since the implementation of CTMSs. It is much easier and more reliable to have all of the clinical trial data in one place. This allows for reliable documentation and proof of oversight and management of the trial for audits and for health authority inspections.
There are many uses of CTMSs in clinical trial management (Table 1). Key uses include country and site status, monitoring reports, timelines, and trial planning. It is very useful to have all monitoring reports, approvals, action items, and observations a consolidated system. This makes it easy to run reports and conduct trending analyses to see where there might be issues.
Status of clinical trial programs with 10-20 different trials needs to be monitored by management, specifically as to whether or not milestones are being met. CTMSs are very useful for reviewing timelines and for financial planning of trials, especially when trials are on the critical path. By having this in an electronic system, management is able to focus on a certain trials status or look at information from a more holistic program point of view.
Basic Structure, Contents, and Functioning of CTMS
Table 2 highlights the basic structure and content of a CMTS. The basic structure starts at the portfolio level and goes to the program, clinical trial, country, clinical research site, and patient levels. Having a system with this much detail is very important because the system has many different consumers who are looking at the data in numerous ways. Staff members who are managing the trials may be looking at the country, site, and subject. Other staff members who are doing analytics do not need that much detail and find the high-level analysis of the trial portfolio available in most CMTSs very helpful. In addition, CTMS is often used to help look at historical data to help plan and to conduct current clinical trials.
Basic contents of CTMS include the general program information with indication/therapeutic area, protocol details and design, site status and information, trial team members, etc. Staff members can filter on these fields and easily generate information at different levels. CTMSs are also a very good tool for tracking health authority and institutional review board/ethics committee submissions and approvals. Tracking these submissions and approvals has been a challenge in the past. Entering the information into a CTMS ensures consistency and makes it easy to track submissions and approvals and ensure all parties are aligned.
General research subject information (non-HIPAA) and team member contact information are also part of CTMSs. The patient information is non-patient specific and covers information such as the date of the first informed consent, the date of the first dose of the study drug, and so forth. It is easy to go into the system and pull information, for example, about when the first patient at a clinical research site in France had the first dose of the study drug. The CTMS includes contact information for the clinical trial team, principal investigator, site, and CRO. The CTMS will provide a list of contacts and much of the background information needed when the sponsor is getting ready to prepare a submission or an inspection.
Day-to-day operations of CTMSs involve many tasks and features including data entry, reporting, and data review. While some systems can communicate with each other, some manual labor may be involved in ensuring that systems are consistent. In some cases, data must be entered manually as it might not be captured in any other location. System syncing with the eCRF, safety database, IxRS, etc. is a major feature of CTMSs. This eliminates human error and makes managing clinical trials much easier.
System oversight is an absolute necessity. Clinical trial teams cannot just rely on the data in CTMS. They must regularly ensure that the data are correct whether they take a risk-based approach or perform 100% audits.
Reporting is another major feature of CTMSs. Management wants to see succinct high-level reports that provide necessary information. Often, these reports are done in an ad hoc manner and are not standardized across clinical trials. Management usually want reports that can easily be used across trials. CTMSs can produce consistent reports that use the same formats and information for different trials and programs.
The Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice E6(R2) emphasizes risk management. CTMS can perform trend analysis such as tracking risks and key quality issues and metrics. This enables sponsors to identify issues and fix them in a timely manner.
Other electronic systems that can be synced with CTMSs include:
- Electronic data capture (EDC) systems
- Safety databases
- Internal and external reporting systems
- Interactive voice response systems
- Departmental databases
- Regulatory repositories.
Syncing CTMSs to other systems provides a very comprehensive look at the different aspects of a clinical trial, acting as a central repository for trial data and reporting. That being said, CTMSs are not the source of all data, i.e., safety reports, but act as a method for central reporting.
In the past, Microsoft Access databases were used to link data. However, Microsoft Access databases are not validated and do not comply with 21 CFR Part 11. This created many issues because the new regulations were rolled out and forced the new generation of CTMSs to be validated. CTMSs may not contain patient data, but they may trigger certain milestones, payments, or inputs.
The CTMSs used at the clinical research site level are similar to those used by pharmaceutical and biotechnology companies and CROs; however, they are not as robust. CTMSs for sites handle functions such as patient management, document repository, compliance, finances, recruitment, and enrollment. The CTMSs used by sponsors and CROs handle payments, finance, site monitoring, site/country trending, future statistical use, and so forth.
Electronic System Requirements
CTMSs and any electronic systems used in a clinical trial must comply with 21 CFR Part 11. Table 3 highlights key parts of 21 CFR Part 11 for CTMSs:
- Audit trail
- Limited access and training
- Input and accuracy of data
- Electronic signatures.
Validation of a CTMS is a long step-by-step process requiring multiple resources and a large amount of documentation, even for a small update to a field or a tab. Changing one form can take weeks. Due to the nature of the long and resource intensive nature of updates, companies will often have a running change log. This would allow the group to not make every small update but wait for a major or required update and then ensure that all of the smaller ones are incorporated.
Every electronic system must have an audit trail that shows what the changes were, who made them, and why they were made. The audit trail should be human readable, which means that anybody should be able to understand the audit trail report. Often, audit trials are documented in large Excel reports, which require extensive subject matter expertise to be understood. An FDA Investigator could give an observation about this if the team is unable to explain to them the changes.
Access to the CTMS, or any electronic system, must be controlled by limiting access and providing proper training to users. A master user list of who had access to the system and when access was granted and removed (if applicable) must be maintained. Documentation of training must be kept in the study files. The first thing that most FDA Investigators will ask is who had access to the data and whether the users were qualified to have that access.
Human error in input of data has always been problematic. Data input is more accurate with a CTMS; however, it is still necessary to ensure that what is input into the CTMS is correct. For example, an FDA investigator could ask for a list of all clinical research sites and clinical investigators. When the staff members pull the list from the CTMS and give it to the FDA investigator, the first thing that they will do is compare it to the study report. Discrepancies would lead to further questioning and would put the team into a difficult position.
There is no consistent way to handle electronic signatures, which must be auditable and within a closed system. Guidance documents from different health authorities are somewhat contradictory on how to collect them, but all have the same intent. There are many internal and external documents that must be signed, which provides a challenge because you can only control the internal ones. For the most part this is quite consistent, but for documents that must be signed by the site, i.e. protocol signature pages or IB acknowledgements, the site may have different processes that may or may not be accepted globally.
Users who are granted access to the CTMS will receive training, and the company will maintain documentation of the training. The U.S. Food and Drug Administration currently accepts this process; however, the European Medicines Agency or Medicines and Healthcare Products Regulatory Agency might be more stringent because they are more focused on the process.
After data input and review, CTMSs are used to get data to the people who need them, including clinical trial teams who need simple reports such as subjects enrolled by clinical research site as well as executive management who need to understand the status of the overall portfolio (Table 4).
Reports need to be able to be generated quickly. Monthly or bi-monthly reporting from a CTMS is a very common practice for senior management review. It is very easy for staff members to generate a report simply by clicking “run,” doing a quick quality control review, and then providing it to executive management. Reports for executive management include:
- Study overview
- Risk management
- Reporting tools.
Often, executive management have questions that require the generation of more ad hoc reports.
Dashboards are a type of report in CTMSs that provide high-level consolidated information. By providing dashboard reports to executive management who want high-level consolidated information, it makes it easy for the trial team to comply quickly. Dashboard reports usually provide colorful status checks with stoplights, pie charts, and so forth. Reports can be customized and provided at the program, clinical trial, or clinical research site level.
A big advantage of CTMS is the ability to merge different datasets from different systems to create new listings. Listings can cross-reference any available data to provide necessary information. For example, if the study team is looking at safety data and protocol deviations, the datasets can be merged and cross referenced to provide detailed information. Listings can also be used for other types of data and medical review, submission documentation, and compiling of multiple types of data for clinical trial management.
CTMSs are critical for daily management of clinical trials. Everything that is necessary for general oversight of trials should be centralized in a CTMS. This makes life much easier for trial teams and executive management, and it requires fewer resources. Reporting is one of the major features of CTMSs. Generating reports through a CTMS is simple, and reports can easily be customized. CTMSs must comply with 21 CFR Part 11. Table 5 provides some resources related to CTMSs.
Clinical Trial Management Uses of CTMSs
- Enrollment statistics
- Country and site status
- Site monitoring
- Team lists
- Electronic trial master file
- Resource management
- Trending analysis
- Risk management
- Reporting tool
- Clinical Investigator management
- Trial planning
- Investigational product tracking and planning
Basic Structure and Contents of CMTSs
- Basic structure:
- Basic contents of CTMSs:
- General program information, protocol details, etc.
- Health authority submission and approval tracking
- Institutional review board/ethics committee submission and approval tracking
- General research subject information (non-subject specific)
- Trial team, clinical investigator, site, and CRO contacts
21 CFR Part 11
- Step-by-step validation process
- Large amount of documentation
- Very time consuming and requires multiple resources
- Must occur for every upgrade of the system
- Audit trail:
- Required for all data points
- Must include:
- Who/what changed the data
- When and what was changed
- Must have all historical changes no matter how small
- Report should be readily available for auditor and FDA Investigators
- Limited access and training:
- Proper training required before granting access
- Maintain documentation of training
- Maintain a master user list of who had access and from when to when
- Input and accuracy of data:
- Data input can be auto-generated from other systems or by manual data entry
- Accuracy depends entirely on data input; however, edit checks can be implemented
- Must be able to export data
- Electronic signatures:
- Signed agreements/signature logs with all people using electronic signatures
- Training, access, and limitations
- Must be auditable and within a closed system
Outputs of CMTSs
- Executive management:
- Study overview
- Risk management
- Reporting tool
- High-level consolidated information
- Status checks:
- For program-, trial-, or site-level reporting
- Listings/merged datasets:
- Listings often used:
- When dashboards are reporting too high of a level
- For regulatory reporting needs
- For comparison to other systems
- Submission documentation
- Data review and medical review
- Compiling multiple types of data for trial management
- Listings often used:
Resources on CMTSs
- Clinical Trial Management System, Wilkipedia:
- Clinical Trial Management System:
- Site monitoring dashboard:
- Guidance for Industry: Part 11, Electronic Records; Electronic Signatures — Scope and Application