Clinical Researcher—January 2018 (Volume 32, Issue 1)
Eric Distad; Laura Eaton
As medical device technology is becoming more and more sophisticated, the need for long-term follow-up in postmarket or late-phase studies is becoming the norm. Regulatory agencies are seeking data on longer-term safety effects—sometimes for the life of the product or patient—and in the future, registries may replace and/or supplement pivotal clinical trials. While that’s a topic for another time, we will focus here on ways to meet compliance targets in the age of technology and patient mobility.
Start With the End in Mind
First, sponsors need to develop the clinical investigational plan (CIP) with the end goal in mind. This means defining in the protocol what lost-to-follow-up (LTFU) really means, so that it can be identified when it happens. For example, is the subject LTFU after missing one or two consecutive study visits, or after multiple phone calls and a registered letter have gone unanswered?
In one long-term weight loss study we conducted, we defined LTFU as when the subject missed the final five-year visit. Subjects could miss several (even consecutive) visits in between; however, we gave them every possible chance to come back, hoping that in the end they might show up.
Other studies may require a tighter definition. For example, many cardiovascular studies depend on data points collected at set intervals to evaluate safety and efficacy, and missing them quickly complicates the analysis. Other examples are studies with interim analyses and/or employing alternative statistical methodologies in which each visit and its associated data points are critical.
Ten-year studies are not uncommon, especially for cardiovascular devices, and these can be extremely challenging due to the age of the patients. Although regulators may only require investigators to confirm the patient’s “alive” status at each visit (even those conducted via phone call), it is also very important to confirm and collect patient contact information at the same time. This should include at least two sources of secondary contact information, as patients may move around a lot or may be placed in long-term care facilities.
In general, proactive planning for subject retention is key to study success. Incentives (as allowed by regulations) to all participants who enroll and complete scheduled visits serve to not only enhance enrollment, but also to aid in subject retention. Depending on the study, on subject requirements at follow-up visits; and on regulatory limitations, it can also be helpful to increase incentive payments slightly for each subsequent visit.
Study engagement is critical to keeping subjects in the study long term, and it can be useful (and less subject to regulatory constraints) to give sites incentives for maintaining subject retention and minimizing LTFU. Consider multiple touch points—including study and intervention newsletters, mobile or desktop apps, websites, e-mails, and social media.
Meanwhile, there is a common misconception that many older patients are not comfortable with technology. In reality, many publications such as newspapers have moved to online content only, and elderly patients are getting their news from smart phones and other handheld devices. Do not be afraid to ask for an e-mail address that can be used for visit reminders or sending study newsletters. In addition, there are electronic data capture systems now that can be synched with subject’s smartphones, computers, etc. for remote follow-up data and visits.
Educate and Collaborate With Sites
Another key tool for mitigating LTFU is site training. It is important to ensure that sites—and in particular coordinators—understand the CIP-specific definitions and requirements around visits and LTFU, as well as the reasons why maintaining follow-up compliance is so important. When coordinators understand this, they are far more likely to work to meet the requirements.
Training should also cover the various tools that will be used in the study to help drive compliance. These should include those available to sites as well as those that the sponsor will be using across the study.
The most effective training is a two-way street; listen to your sites’ reports of what they are seeing, what they say they need, and the ideas they share. Lastly, the training and the tools used should be proactive, transparent, and ongoing throughout the study. As part of this flow of information, it will be important to rely on the clinical research associates and overall monitoring strategy to identify trends and potential issues with follow-up compliance as early as possible.
Staying on Plan
If you’ve followed all of these suggestions and your rate of compliance with follow-up is lower than desired and/or you are losing subjects, what can be done to try to locate lost subjects? Beyond pursuing leads from the subject and caregiver contact information and sending a certified letter, you can take some additional steps (which ideally were outlined in the CIP).
Searching for the names of both the subject and known caregivers could help with finding current contact information. Often, sites can help with these searches by using their databases and broader consents, but you will, of course, need to include those efforts in the site contract and reimburse them appropriately for the work.
You will also need to search death certificate databases as a final step. If you prefer to outsource this effort, there are companies that specialize in locating subjects LTFU. These companies will use the same tools available to you, but bringing them onboard either to manage noncompliance and potential LTFU proactively or in real-time can help mitigate what otherwise could be more severe if handled reactively late in the study.
In conclusion, the need for long-term follow-up data is becoming the norm for many indications and therapies. Whether those requirements are mandated by regulatory agencies or required for therapy adoption, it is critical that not only the scientific aspect of the CIP be well thought out, but the long-term follow-up strategy as well.
It can be helpful to partner with consultants and/or organizations that have experience with these types of studies in the specific patient population and therapy that you are evaluating. Taking advantage of their experience across numerous studies will likely limit issues down the road.