Five Ways to Mitigate Risk Using a CTMS

The clinical development of products for patients worldwide faces intense scrutiny. These products are required to be safe and effective for patients to treat the indication under study. The products should not cause negative side effects that outweigh their clinical benefits, adding unnecessary risks to the patient population.

Risks exist throughout the product development process, outside of pure patient safety. To get a safe and effective product approved for use by patients, risks need to assessed and managed. Sponsors must endeavor to reduce or eliminate any needless risks that may impact the product development process. As authorities are tasked with protecting the public, global regulatory agencies have instituted requirements and recommended guidelines for sponsors to ensure patient safety. Sponsors must implement processes and procedures to protect patient safety and follow the guidelines as closely as possible to give their products the best chance for success through the scrutiny during regulatory evaluation.

No matter how closely sponsors (and the CROs that support outsourced studies) follow the guidelines, product development has risks. The sponsor goals are to have risk mitigation processes in place during the conduct of their clinical programs. A CTMS is one of the eClinical solutions that can be put in place to streamline: 1) local and/or global study management 2) assist in identifying any risks and 3) have a documented risk mitigation plan and process. Below are 5 ways a sponsor can mitigate risk by using a robust CTMS.

Protocol Deviations

Protocol deviations happen in every study because, well, nobody is perfect! The FDA requires that when uncovered, deviations are documented, tracked and resolved. Furthermore, ICH E3 outlines “protocol deviations once uncovered, can then be categorized as important or non-important.” (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8238759/) While sponsors and CROs at times use different terminology, the ICH E3 uses “important,” “major,” “critical” and “significant” as synonyms when referring to important protocol deviations.

Regardless of the terminology used by your organization, these deviations do need to be documented and tracked with defined owners. Important deviations must also be included in the Clinical Study Report. Many companies still use “trackers” or Excel spreadsheets to track these, which can be tedious. Having a CTMS with robust and configurable Protocol Deviation tracking allows sponsors not only to document the Protocol Deviations, but also provides your company flexibility in the configuration of naming and classification.

Too many protocol deviations found at a specific site can put a sponsor at risk of not meeting a study endpoint. A well thought out protocol deviation offering in a CTMS allows sponsors to look at trends within and across sites, as well as roles. Protocol deviation KPIs can have thresholds that serve as a warning of potential risks and allow for early intervention. An easy-to-use CTMS affords the CRA and/or the study team, including the Medical Monitor, the ability to identify these “signals” and recommend remedial training for relevant investigative site personnel or a CRO or study team member.

Milestones

Life is full of milestones. It could be a marriage, the birth of a child, a birthday threshold moving into a new decade, or running your first 5K or marathon. Friends and family may say “Wow congratulations, what an accomplishment that you met X milestone!” Every person defines what they consider the milestones that they want to measure and achieve in all aspects of life.

Just like our personal lives, the conduct of clinical programs and clinical trials have their own milestones. These are generally defined by the company and management teams that oversee these studies. The FDA does not define or require the reporting of milestones, but they are used to track the progress of trials once defined. Most sponsors have some standard milestones that the whole industry tracks and many times use some of those milestones to bid out studies to CROs. These milestones include:

• Protocol finalized
• Date 1st site initiated
• First Patient First Visit (FPFV)
• Last Patient Last Visit (LPLV)
• Database Lock
• Date of Final Clinical Study Report (CSR)

These are examples are common study level milestones used by sponsors and CROs. Sponsors typically have many more milestones to track that are much more granular and often categorized in trial execution. These might include milestones for Feasibility, Enrollment, Monitoring, or Closeout, and will vary from one organization to the next.

A CTMS is the aggregator of all study information if used properly (and if your company dumps those trackers!), including all study milestones. A good CTMS allows for configuration of company-specific milestone templates.  These templates can be applied to studies (and changed as needed) to allow visualization of where the study stands with respect to those milestones. Milestone statuses are typically needed by management level personnel and may be related to a payment of a particular vendor, a development partner (who may have a Milestone payment in their agreement) or may be critical for investor relations and fund raising.

Having this in a CTMS is critical for oversight as risk arises when milestones ares not documented, tracked inaccurately and/or are overdue. The better CTMS offerings allow sponsors to further classify milestones based on risk that can allow for easy visualization and like the protocol deviations allow intervention when needed to ensure milestones are being met.

Monitoring Visit Documentation

As a former Clinical Research Associate (CRA), one of the most critical roles on the study team is the CRA who is assigned sites for a study (or studies) and serves as an “overseer” for their sites and site personnel. They ensure that well qualified investigators are selected and that the investigative staff assigned are trained before any study procedures are executed. Additionally, they are tasked with verifying, reconciling, and returning Investigational Product (IP) as well as ensuring the site is complying with the protocol as required on the 1572 and following FDA and other global regulations for study conduct and reporting.

Regulatory agencies require documentation of oversight related to investigative sites and critical documentation related to monitoring visits for every visit to each site. As a rule, most sponsors require the following:

• Confirmation Letter – This outlines the date of the visit (in person or remote) and any planned activities that will be conducted, as well as any open items that will be covered during that visit.
• Monitoring Visit Report – This outlines 1) who was met with during the site visit 2) what locations did the visit (as there could be multiple locations where patients are seen as well as storage of IP, etc), what activities were completed during visit/what new or open activities or action items occurred during the visit that need follow up 3) a standard checklist for each visit type for all sites of what was covered (with any comments) 4) which subjects were reviewed 5) the length of the visit and 6) any co-monitors from the sponsor or CRO joined the visit. This is maintained by the sponsor or CRO in their Trial Master File as required by the regulatory authorities.
• Follow Up Letter – This letter is sent to the Principal Investigator (PI) and other site personnel, such as the study coordinator, and summarizes many of the items from the Monitoring Visit above. It serves as formal documentation of what occurred during the visit for the sponsor and must be kept in the investigator site files.

While some sponsors still write these documents in Microsoft Word, it is becoming more common for sponsors to pick a CTMS solution with a robust offering for documentation of all information around the monitoring visit. There are significant risks of FDA findings when reports are completed in isolation and not in a robust CTMS with trends and signals missed that might identify a problem which needs intervention in a study. There could be findings that highlight the need to implement a protocol amendment.

Without a CTMS there is no way to easily identify trends and risks. Companies that decide not to implement a CTMS to solve this challenge are just “checking the box” and introducing risk to their company.

Activity Plans

The concept of activity plans may be foreign to some sponsors and CROs, but they can be a helpful way to leverage a CTMS as an aggregator and reduce risk in studies.  Some companies look at these as “job aids” or “checklists” that are used to manage a particular set of tasks. An example of an Activity Plan could be for a study’s Closeout Visit.  A CRA who was never assigned to that study, due to team availability, is asked to go to the site to perform a Closeout Visit. That CRA needs to understand all the items which they need to complete while they are at the Closeout Visit. To do so, they could either flip through a large, unwieldy manual to find the document they need OR they can simply check the CTMS for the Activity Plan of what needs to be completed:

• Review any last patients and resolve any outstanding queries. CHECK.
• Remind the PI that they need to submit a formal closeout letter to their IRB/EC. CHECK
• Review and reconcile any last IP and ship it back the IP depot for destruction. CHECK
• Ship back any other supplies used for the study to the relevant vendor. CHECK
• Complete final closeout letter and Closeout letter to site. CHECK

This is an example of one Activity Plan that a CTMS can offer which can be used to improve study compliance, reduce risk and allow study leads & managers to see which activities have been completed. The Activity Plans can be configured at the Study, Site and Country levels, such as the production and packaging of IP. Any missed steps in Activity Plan completion can introduce risks of protocol non-compliance and deviations.

Investigator Payments

Without investigators to run the studies, there would be no patients to take the IP to test the therapy, and the whole process collapses. As a former study manager, I had to negotiate many investigator contracts and budgets. This was all in the days of paper back in the 1990s (and sadly many still do it this way) and tracking all of the contracts, budgets, patients enrolled for investigator payments, drawn down accounts of $$ based on enrollment forecasts, etc. was all a challenge.

Fortunately, CTMS can change a lot of this. Contracts and budgets can be collaboratively authored and approved virtually without large numbers of emails, budgets can be forecast, and investigator payments set up by milestones, visits and or procedures. The better systems have a lot of flexibility and can do this without paper, including approvals!

Some sites only do work on Clinical studies. Making sure payments are made on time is critical to get paychecks to their site personnel and stay in business. A big risk from the days of paper was investigators not being paid on time, and I have heard stories of sites deciding to no longer participate in clinical trials due to administrative problems with payment. This limits the number of qualified sites that can be used to recruit patients for the treatment of a particular disease indication and introduces the risk of late study completion. A CTMS can aggregate all payment information, giving study teams and CRAs real time updates. Should site personnel contact the project team, a CTMS can allow administrators to assure sites that they are being paid promptly and/or investigate why a payment has not been received.

There are certainly many more risks in a study or clinical program than the 5 outlined above, but most clinical teams would agree that these 5 are those most critical. Regardless of the study size, sponsors should be implementing and using a CTMS rather than spreadsheets. Even when outsourced to a CRO, a sponsor should consider having their own CTMS integrating key data from the CRO’s CTMS. At the end of the day, the sponsor is the one accountable to the regulatory agencies and responsible for the approval (or non-approval if risks are not managed and overseen well) of the product(s) under study…and you and your company want to be on the winning side. So if you don’t have that CTMS, get one. If you have one that is homegrown or dated, maybe it is time to modernize with a new solution to minimize your regulatory risks.