The differences and similarities between long-term follow-up and phase IV trials
The ins and outs of clinical trials and their phases can get complex, particularly when dealing with high-risk treatments and therapies. Regardless, there are several measures put into place by regulatory bodies, such as the FDA, the ensure that no matter the risk level, treatments, therapies, and drug products going to market are properly investigated and understood. This is most commonly done via phase IV trials.
The FDA commonly defines phase IV trials as “post-marketing studies, which are conducted after a treatment [which are] approved for use by the FDA, [which] provide additional information including the treatment or drug’s risks, benefits, and best use.” The FDA also states the primary purpose of these studies as being for “safety and efficacy.” Phase IV trials are typically the last step in a common 4-phase process.
Alternatively, some trials require additional patient monitoring to be set up before going to market. This can be done through long-term follow-up studies which are often confused with or grouped together with phase IV trials. This blog outlines the key defining factors of these two types of studies and identifies where the similarities between the two lie.
Phase IV trials:
The FDA outlines the typical formula for designing and executing clinical trials for a new drug or therapy as:
- Phase I, which can last several months, for the purpose of investigating safety and dosage,
- Phase II, which can last several months or up 2 years, for the purpose of studying safety and efficacy,
- Phase III, which can be anywhere from 1 to 4 years, to has the purpose of studying efficacy and monitoring adverse reactions and typically takes place with a significantly larger patient population; and
- Phase IV, which can last many years, to study safety and efficacy in large patient populations after FDA approval.
Some phase IV trials are part of the post-market surveillance (PMS) stage once a drug, device, or treatment has been approved by the FDA. The PMS stage is defined by the FDA as being a time when they monitor “adverse events such as adverse reactions and poisonings. The Agency uses this information to update drug labeling, and, on rare occasions, to reevaluate the approval or marketing decision.” Another similar definition comes from the National Cancer Institute, stating that a phase IV trial is “a type of clinical trial that studies the side effects caused over time by a new treatment after it has been approved and is on the market. These trials look for side effects that were not seen in earlier trials and may also study how well a new treatment works over a long period of time.”
These trials are typically low-risk, with minimal interventions, and involve monitoring patients who have already received a specific treatment, drug product, or therapy for a predetermined amount of time to carefully assess any side effects or changes in health that become apparent with continued, widespread use of the product.
Long-Term Follow-up Trials:
The FDA defines long-term follow-up in clinical trials as ”extended assessments that continue some of the scheduled observations of a clinical trial past the active follow-up period, and are an integral portion of [some studies]. LTFU observations are important to monitor long-term safety of [..] products.” Researchers Hill, K. G., et. al., found some benefits of long term-follow-up include “the capacity to examine program effects across multiple later life outcomes, the ability to examine the etiological processes involved in the development of the outcomes of interest, and the ability to provide more concrete estimates of the relative benefits and costs of an intervention.”
In most scenarios, a long-term follow-up study is an extension of a clinical trial where it becomes obvious there is a need for continued collection of patients’ health information and feedback directly after participation. For example, patients who have received oncology treatment for cancer may complete their treatment in the active care portion of that trial and then participate in the long-term follow-up study where they are asked to provide health information for months or years after their treatment. However, it is common to run LTFU trials as standalone studies which incorporate different tools and designs necessary for proper study execution.
One of the most widely accepted reasons why LTFU is important in clinical research is to ensure and validate long-term safety and effectiveness for all patients who may receive this particular treatment or intervention, such as side effects, interactions with other treatments, etc. There are also several instances where the FDA requires long-term follow-up studies for specific treatments to be completed in the trial process for a magnitude of reasons.
Differences and Similarities:
By definition, Phase IV trials always happen after once a drug or therapy has been approved for clinical use, while long-term follow-up studies can occur at any stage of clinical testing. Some trials can even have LTFU built into the protocol. For example, a phase III oncology trial may include a long-term follow-up arm in the initial study design in order to properly record all necessary data.
However, the technology, study design, timeline, and protocol are likely very similar between the two types of studies. Both studies monitor patients for typically extended periods of time in a manner that often does not require patients to be in person. Studies can use technology to check in with patients via telemedicine, administer virtual surveys to collect ePROs, deploy mobile nurses/phlebotomists to collect samples, utilize local care facilities to conduct necessary testing, scans, etc, and more.
Regardless of their differences, both studies look to collect crucial data on patients' safety, long and short-term side effects, and any other interactions or implications that may be associated with a specific therapy, treatment, or drug product.