What is a CTMS - Clinical Trial Management System?
For proper context, before we delve into the question of what a Clinical Trial Management System (CTMS) is, let’s begin with a brief recap on the history of clinical trials.
The History of Clinical Trials
According to A. Bhatt writing on the evolution of clinical trials in the “Perspectives of Clinical Research”, clinical trials have had a fascinating evolution, with the first recorded trial dating back to biblical times. One of the most famous and historic was that of James Lind in 1747, whose scurvy trial contained most of the elements of a ‘controlled’ trial. It wasn’t until 1946 though that we saw the first randomized control trial carried out by the UK MRC (Medical Research Council). To this day, this streptomycin in pulmonary tuberculosis trial is considered truly ground-breaking. With intelligent design and implementation, systematic enrolment criteria and data collection, this was highly sophisticated in comparison to the ad hoc ‘trials’ that had been conducted previously.
It’s not just science and drug discovery that have been on an evolutionary journey though – so too have ethical and regulatory standards. The first evidenced international guidance on the ethics of medical research involving participants was formulated in 1947, the “Nuremberg Code”. It was from the origins of this Code that Good Clinical Practice (GCP) was formed. However, other parts of the world began to create their own sets of principles and guidelines, leading to confusion within the global market. This was solved in 1996 when a set of conferences brought various global guidelines together to create one harmonized set of principles, known as the ICH – GCP. Today the research healthcare industry conducts clinical trials in accordance to this set of international ethical and scientific standards.
The regulatory guidance has evolved along with the evolution of ethical principles and values throughout the health sciences industry. The Food & Drug Administration (FDA) was founded in 1862 as an Institution, later becoming a government enforcing agency in the early 1900’s. The UK counterpart, the Medicines and Healthcare Products Regulatory Agency (MHRA) was founded in 1918. A pan european body, the European Medicines Agency (EMA) was formed in 1995. These regulatory agencies operate with the same aim and ethos – to facilitate scientific excellence in medicine, while ensuring patient safety and efficacy. All drugs and certain medical devices need to be approved by bodies such as these and issued a license before they can be made available in the marketplace for patients to use.
Licensed drugs and medical devices depend on the outcomes of clinical trials that have been conducted in accordance with the principles of Good Clinical Practice.
So What is a Clinical Trial Management System (CTMS)?
This commonly asked question is not simple to answer owing to the lack of a widely agreed definition of the scope and capabilities of a CTMS. According to Wikipedia, a Clinical Trial Management System is a software system used by biotechnology and pharmaceutical industries to manage their clinical trials. This definition is both broad and yet incomplete. Broad due to the large scope of a CTMS – a system to manage many clinical operational processes, store enterprise information about a company’s medical product assets (drugs, medical devices), and to act as a central repository for the organization’s key information across its clinical trial portfolio. It is incomplete from the viewpoint that companies running a large number of clinical trials can use up to 10 different systems in a clinical trial, with each system serving a specific purpose.
Management systems that encompass a large number of operating processes have fewer constraints compared to systems with a strict set of functions and outputs, like an EDC system. In an EDC system, there are well defined functions, e.g. design a case report form (CRF), capture clinical data, encode data, validate data, resolve data queries, and export data for statistical processing in a standardized data format (CDISC). In contrast, a CTMS system has a broader scope and several external outputs, some of which are part of the regulated dataset and submission, and others that are not, but provide management control and governance of trials.
Many of the management, operational, administrative, and clinical processes advocated in GCP are defined and supported by a CTMS, which places that system firmly in the center of an ecosystem of associated clinical applications.
The Ten Essential Capabilities of a CTMS
1. Central Repository of clinical trials and associated product assets, providing an overall definition of these trials.
2. Trial Planning and Design across the entities involved such as countries, sites, investigators, and third party organizations, facilitating tracking and management of key milestones associated with a clinical trial.
3. Regulatory Approval Tracking of Institutional Review Board (IRB) and Ethics committee (EC) approvals.
4. Team Management – clinical trials are a large undertaking, especially in phase 3 trials, and the roles and responsibilities of all participants in a trial need to be clearly defined and tracked for the duration of the trial.
5. Supplier Management – trials can have multiple suppliers engaged to provide services, including contract research organizations (CROs), laboratory services, specialist providers (e.g. medical imaging), investigational product supply, and logistics to ensure trial supply is managed across participating sites. The sponsor of the trial is responsible for the oversight (governance) of the trial across the entire supply chain.
6. Clinical monitoring – a key function of a CTMS is to support clinical monitoring workflows, which is one of the main activities performed by clinical research associates (CRAs). The monitoring plan determines many of the key quality criteria that CRAs need to assess on an ongoing basis to ensure that the conduct of the trial continues to meet regulatory, ethical, and patient safety standards.
7. Investigator Payments – for tracking the financial payments that are due to investigators and other third parties contracted to provide medical services at participating clinical sites. The US Sunshine Act requires disclosure of payments made to US physicians and university teaching hospitals by organizations in the healthcare industry to health care providers.
8. Issue Management – While conducting clinical trials, problems and issues that arise need to be managed and resolved. Issues such as protocol deviations or other study level, country specific, and site level issues need to be tracked and resolved according to GCP to ensure that ethical, professional, and patient safety principles are adequately maintained.
9. Essential Document Tracking – Historically CTMS systems have been designed to track and store a subset of the documents generated during the course of a trial. Over the last decade a new breed of system – the electronic Trial Master File (eTMF) – has emerged, and this based on the efforts of an industry forum that defines a recommended filing structure for the full list of critical documents for a clinical trial.
10. Business Intelligence – Reporting and operational metrics provide performance management, including the ability to compare these metrics across a range of studies. The ability to adjust trial conduct based on having a real time view of progress (e.g. state of clinical site initiation, of patient enrolment, and so forth) accelerates speed of decision making to support project management and study conduct. Additionally, the ability to view a centralized list of all issues and associated mitigating actions increases quality and reduces enterprise risk. Further, by collaborating with suppliers who use a shared CTMS, more effective governance and oversight is available to Sponsors, ensuring they maintain effective control in compliance with GCP.
What Other Systems are Used in Clinical Trials and How Does a CTMS Interact with Them?
As they involve significant resources, clinical trials make use of several systems to manage overall processes, including:
- Clinical Data Management (CDM/EDC) –- capturing structured patient data as specified in the electronic case report forms (eCRF) from each of the clinical sites in the trial. A protocol defines the scientific data that needs to be collected to determine both the efficacy and safety of the investigational drug/device being evaluated.
- Patient Randomization and Supply Management (RTSM) – Regarding the allocation of a treatment to a trial patient, clinical trials are usually run in a randomized and “blinded” mode to prevent bias being introduced in the trial. Treatment can consist of the experimental drug compared against a placebo and/or a comparator (currently marketed) drug. RTSM systems are also used to ensure clinical sites receive appropriate drug supplies based on consumption to prevent overage and wastage.
- Medical Imaging – medical imaging is used to analyze the progress of treatment for various therapeutic conditions such as oncology (tumor size), bone density measurements and internal organ analysis. In many protocols, the primary endpoint being assessed is an imaging endpoint, increasing the importance and criticality of imaging operations performed in such trials.
- Patient Reported Outcomes (ePRO) – An increasing amount of supplementary data can also be collected from patients participating in a clinical trial as direct information supplied by the patient without an intervening interpretation. This can augment the highly structured and scientific data being collected via the eCRFs.
- Pharmacovigilance (safety) – safeguarding patient safety is a key principle in running regulated clinical trials. Safety events have to be recorded, monitored, and triaged. Serious adverse events need to be reported to the regulatory authorities with supporting medical opinion on causality.
- Regulatory – systems designed to support regulatory affairs processes including interactions with regulatory agencies, trial registrations, licensing and creation of the drug submission documentation.
- Biostatistic – statistical programs that are used to analyze clinical data and determine the efficacy of the treatment under investigation in addition to the safety profile.
- Quality – different aspects of quality are managed within all the aforementioned systems however it is common for an organization to have an independent quality system to manage general quality aspects that are not managed within a single system such as supplier audit management issues, operating process deviations, manufacturing issues, etc.
The necessity to utilize many systems in large clinical trial programs means that clinical trial information becomes spread across a large number of systems. While each system has been designed to perform a specialized role, there is common information that is required by several systems, and this is best managed by integrating these different systems as opposed to duplicating information repeatedly across this IT estate.
The definition of the term “system of record” is used to designate a system as the primary source and custodian of a piece of data which is then shareable with other systems that depend on that information for their own purposes. The CTMS system is a system of record for key clinical trial information.
Figure 1: CTMS and the eClinical ecosystem
Seven Frequently Asked CTMS Questions
1. When do we need a CTMS?
A CTMS can be used across the entire clinical portfolio from Phase 1 to Phase 4 studies. The investment and implementation does however depend on the problem being solved – from managing a range of different assets and associated clinical trials for a large company to managing a single high value asset and overseeing outsourced clinical trials. Considering the number, size, and scope of clinical trials and their associated operational resources that need to be managed along with the level of automation desired usually dictates the optimum point at which CTMS systems have been historically implemented.
The regulatory landscape however has been changing, introducing increased focus on how GCP oversight is managed by a product company, even for those outsourcing their clinical trials to suppliers. For smaller organizations, the ad hoc management of clinical trials through the use of manual and semi-automated methods such as spreadsheets and similar desktop tools exposes the organization to levels of enterprise risk that can be easily overcome with the implementation of a modern CTMS. Service organizations (CROs) will manage outsourced clinical trials on behalf of a range of product companies, and desire the process automation and efficiency that a true CTMS solution provides for clinical operations and study management.
2. What happens to the data in a CTMS after a clinical trial is finished?
CTMS systems are “enterprise” systems. Usually the data in a CTMS is retained indefinitely as it reflects the collective clinical trial experience along with valuable associated product assets, and becomes an effective knowledge base for the organization. In essence, the information in a CTMS represents the “GCP execution record” of where and how the clinical trial has been run, with evidence of performance metrics and any clinical quality issues that were encountered and mitigated. Past experience can be reviewed and used to improve upon how future trials are run.
3. If we outsource clinical trials, is a CTMS still required?
A CTMS will support the company’s business case for maintaining a high quality and complete dataset of trials performed for each of their assets. The responsibility for a clinical trial remains with the Sponsor of the trial, even if aspects of the clinical trial are partially or wholly outsourced to service providers. Outsourcing does not diminish this responsibility, and Sponsors are required to demonstrate effective governance and oversight of their clinical trials. The success of many smaller biotech companies is dependent on making breakthrough discoveries in science and new treatments, and demonstrating this success becomes evident through their clinical trial outcomes. Further investment deals and potential licensing partnerships with larger biopharmaceutical companies are contingent on having high quality data to substantiate the results of clinical trials which have been performed.
4. Are CTMS systems expensive?
They do not have to be. Many legacy systems were designed having a large cost base associated with their technology due to implementation complexity and ongoing maintenance. Modern cloud systems have changed this cost profile significantly, and greatly increased the usability. When evaluating CTMS costs, companies should model the cost of ownership as a company wide investment and not just the cost associated with a single clinical trial (as is currently done for many other systems (i.e. EDC, Imaging, RTSM and ePRO). In fact, the unit cost per trial to leverage a CTMS is generally much less than the comparative unit cost of other aforementioned systems. PHARMASEAL’s Engility® CTMS provides a software as a service (SaaS) subscription pricing model making an enterprise CTMS affordable to any size of organization, addressing the smallest of non-profit research facilities up to large-scale efforts having tens to hundreds of trials running concurrently.
5. Does a CTMS need to be validated?
CTMS systems contain important information regarding the GCP conduct of a clinical trial, recording important decisions being made during study planning, execution and close out.
Depending on the scope of data and the operational processes supported, many companies will require CTMS systems to be validated under the same industry regulations as other eClinical systems, such as FDA 21CFR11 and “computerized systems used in clinical trials”, MHRA “Computer System Validation,” and ICH E6 (R2).
6. How long does it take to implement a CTMS?
Depending upon factors such as the size of the organization, number of people to be trained, number of clinical trials supported, operational readiness, and maturity of the organization, CTMS systems can be implemented within the timeframe of a number of weeks to several months.
7. How does a CTMS co-exist with other systems used in clinical trials? One of the key benefits of implementing a CTMS is to realize the operational and strategic benefits of centralized information management and clinical process automation. When CTMS systems are integrated along with other eClinical systems, this benefit is extended across the IT landscape and reduces data duplication, improves real time information management, visibility, and decision making.
An Integrated View of Clinical Operations
The Clinical IT applications that have emerged over the last 3 decades have predominantly mirrored individual functional needs (e.g. capturing clinical data, statistical analysis, managing a trial, managing essential documents, study startup, randomizing patients, managing safety, and pharmacovigilance). While this has provided for required automation needs in these functions, it does not always address the full scope of enterprise information needs of these organizations in a cohesive and elegant way, ultimately ending up inhibiting optimization and business agility.
When applying principles for the design of an enterprise architecture that underpins and transforms a business, consideration of four different perspectives are necessary:
- Business processes
The PHARMASEAL Engility® Trial Management Platform delivers an enterprise view of clinical operations management, where common processes are consolidated in the same platform as opposed to separate applications. This approach:
- Allows common information to be defined once, reducing data duplication.
- Promotes the integration of clinical operational processes around a common information and technology model, supporting application consolidation.
- Simplifies the technology and applications so that the number of systems is reduced, allowing multiple stakeholders to access different business processes based on their roles and responsibilities.
- Provides an enterprise view of clinical operations satisfying both operational and strategic needs of the business.
The Engility® platform, initially released in June 2019, provides an integrated management model encompassing clinical trial management with the associated trial master file document storage and management. For many SME companies this provides a single solution to address two historically separate business applications, becoming a basis to transform the traditional approach of clinical trial management.
Future clinical trials require flexible operating models to support different study designs such as decentralized clinical trials, centralized vs. remote monitoring, risk based monitoring, and fluid supply chains with stronger collaboration. Technology systems become more useful as they address the needs of these trials of the future. Delivering flexible and adaptive trial management solutions is the core mission of PHARMASEAL.