Phase I-III randomized controlled trials alone are not generating enough data to extrapolate conclusions and theories about therapeutics to the global population. Not all drugs demonstrate the same efficacy in the real world as shown in the clinical trials. Because of this, we are seeing a rise in long-term follow-up (LTFU) studies that follow patient responses to a given treatment over five, 10 or 15 years, depending on the treatment.
“Not all drugs demonstrate the same efficacy in the real world as shown in clinical trials. Because of this we are seeing a rise in long-term follow-up (LTFU) studies that follow patient responses to a given treatment over five, 10 or 15 years.”
LTFU clinical trials: What to know
LTFU studies are particularly important for therapies that provide long-acting changes in the human body, as is the case with newly developed cell and gene therapies. Indeed, the European Medicines Association and U.S. Food and Drug Administration regulations require 10- to 15-year follow-up studies for cell and gene therapies, which, in part, is driving increased demand for LTFU studies.
Moreover, some drugs coming on the market display subtler differences in their effects, meaning that therapeutic benefits over comparable drugs are often unapparent unless longitudinal patient outcomes are measured. LTFU studies are therefore vital for generating real-world data that tracks longitudinal patient well-being. Coupled with this, LTFU studies are adding to the methods of patient care, with an increased interest in clinic research as a care option, a term also known as CRAACO.
Overcoming the challenges of LTFU studies with planned simplicity and flexibility
Designing an LTFU study means planning in unchartered territory. Study designers and orchestrators must be able to:
- Work with shifting regulations on how studies are performed in different legal systems
- Prevent business mergers or changeover of personnel from having a major impact on studies
- Keep patients engaged in the study and prevent high dropout rates
An LTFU study can last from five to 15 years, meaning that it is crucial to incorporate a plan for managing change in any study design. Including the subject matter experts—from medical advisors to regulatory experts—at the start of the planning phase helps ensure flexibility is embedded into the study design from the onset.
There are three important considerations to note when planning LTFU studies:
1. Balancing regulatory requirements
Some of the regulations around electronic data in LTFU studies can be challenging. For example, there are major industry-wide challenges around legal access to electronic patient healthcare records in different countries, especially outside the U.S. where patient data privacy laws are often somewhat stricter. Therefore, it is important to consider what the stringency of those laws may be five, 10 or more years down the line and how they may impact the LTFU study. In other words, be prepared to account for cultural and regulatory differences around the world.
2. Planning for change
With the ability to update systems on a yearly basis, LTFU studies are well equipped to react to industry changes, such as new technologies or regulatory updates. When decisions are made, it’s important to clearly document why and what decisions were made to provide clarity in retrospective reviews five, 10 or 15 years down the line.
From a data perspective, it’s important to keep procedures simple. Collecting only the data you need, as well as prioritizing safety and efficacy, will help to keep data sets and study outcomes manageable. It’s also important to decide how data will be collected, stored and analyzed throughout the duration of the study. Studies must have well-organized, legally compliant and secure databases throughout the LTFU study. With vast amounts of data being collected, huge delays are possible if data system organization is left until the end of the study.
3. Minimizing the burden on patients
An important aspect of any LTFU study involves asking difficult questions: What data is needed? What can we expect of patients and what lengths will we take to produce the required LTFU study data?
The aim is to identify what data is collected, how it is collected and by whom. Database designers, medical and clinical staff, and safety and operations teams will therefore need to work very closely together to ensure the minimum data is collected to make sufficient therapeutic conclusions at the end of the study. Marketing teams or scientists aligned with medical affairs, for example, might ask for additional data points to be captured to meet their own needs, such as marketing claims or wanting to present at a scientific conference. Therefore, all the participating parties need to agree and understand the minimum and optimal data requirements while maintaining patient engagement and meeting regulatory requirements.
The importance of patient-centricity in clinical trials
By far, one of the biggest issues that LTFU studies face is patient retention. Almost everything in how the study is designed must consider the impact on patients.
Making the studies patient-centric brings CRAACO to the forefront and puts people at the heart of studies. A positive effect of this is to help patients create a greater sense of engagement in their study, reducing the possibility of patient dropout. Moreover, it helps bring equity of access to trials to a wider patient population, critical to ensure the validity of the approach to clinical practice. So how can designers make LTFU studies about the patient?
1. Facilitating patient involvement in LTFU studies
Fostering enthusiastic patient involvement is the key to all LTFU studies. Therefore, it’s important to understand the barriers that may keep potential patients from participating in an LTFU study and what strategies designers can use to minimize these barriers and encourage active participation.
For one, there’s the trial length. Participating in an LTFU study can disrupt a patient’s life over many years, even if the decentralized clinical trial (DCT) methods like digital technologies are introduced to reduce the burden on patients. Oncology has specific issues in this regard. If someone is diagnosed with a cancer, then a common rhetoric is that the patient must “fight” against the cancer. If they win the fight, then many patients understandably won’t want to talk about it for another 10 years and be reminded of the illness.
One approach to overcome hesitancy in patient participation in oncology LTFU studies is to help patients understand the social benefits. This could include providing information about how a patient’s data will help future patients, shifting the emphasis from putting a successful cancer fight behind them and more to the tune of “I’ve survived—what can I give back to help future patients?” It is often with this similar societal perspective that citizen science projects have success recruiting volunteers.
“One approach to overcome hesitancy in patient participation in oncology LTFU studies is to help patients understand the social benefits. This could, for example, include providing information about how a patient’s data will help future patients…”
Alternatively, many patients are drawn to a strong, aligned patient community gained by participating in an LTFU study, for example, over Facebook or other social media platforms. These patient communities can often provide some form of emotional support during cancer treatment, helping patients who are geographically distant feel more connected to others going through the same experiences.
2. Maintaining patient engagement in studies
As well as effective recruitment strategies, LTFU studies must have inbuilt solutions to keep patients engaged. DCTs provide several effective ways to reduce patient burden and dropout.
Firstly, studies can be siteless and involve purely remote methods of data collection, eliminating the burden on patients to travel to sites every few months to share data. This is especially important in removing economic barriers to participation.
“As well as effective recruitment strategies, LTFU studies must have inbuilt solutions to keep patients engaged.”
Whether on-site, fully remote or a combination of the two, LTFU studies must have solutions that make it easy for patients to report their data that are as burden-free as possible. This is crucial for retaining patient engagement in studies. The methods of data collection must have the least amount of interruption to their daily lives, making it easy and fast for them to report.
The right clinical research organization (CRO) for your LTFU study
There are different aspects to consider when assessing the suitability of a CRO. Firstly, larger CROs are often more stable and perhaps more likely to remain in business for the duration of the study. Secondly, CROs are very experienced with staff turnover and the advancement of technologies, meaning the constant need to adapt isn’t new, and it should already be built into their business model.
Ultimately, the real strength of the patient-centric approach is its focus on the patient rather than on a trial site. It incorporates elements of DCT design and uses appropriate systems for data collection and patient contact rather than relying on local sites. Using decentralized systems of data collection and implementing CRAACO increases the chances of LTFU study success while also providing patients access to new and developmental therapeutics and the support structure of a large-scale study.