What are Adaptive Clinical Trials?
The clinical trial industry is becoming more open to the idea of adaptive study designs (adaptive clinical trials) to encourage better research outcomes for lower costs. The Food and Drug Administration (FDA) defines an adaptive clinical trial as one that allows for changes to be made to one or more elements while it is still ongoing, based on preliminary subject data analysis. This preliminary quantitative analysis conducted is termed interim analysis, which may assess baseline, safety, efficacy, pharmacokinetics, pharmacodynamics, or biomarker data.
Based on these early results, the study team can choose to enact one or more of their prospectively planned modifications. In contrast, traditional or non-adaptive clinical trials are static in that they’re not designed to accommodate opportunities for future changes. It is important to note that although not every planned modification might stay a feasible option, adaptive clinical trials do not allow for any unplanned changes to be made, as this would invalidate the study results.
Advantages of Adaptive Designs
The goal of adaptive clinical study designs is to reduce costs, increase efficiency, and maximize results for clinical trial sponsors. In addition to the statistical advantages this type of study design provides, there are also ethical benefits over non-adaptive studies. For example, if interim analysis of data reveals a trial has little chance of demonstrating effectiveness, an adaptive trial can be stopped early to prevent exposing more patients to unnecessary risk. This then frees them to seek more successful alternative therapies. Adaptive clinical trials also have the advantage of conserving and redirecting resources. In the case of dose selection studies, if one treatment arm shows comparatively underwhelming efficacy, an adaptive design can prospectively plan for that arm to be removed altogether. With this flexibility, sponsors can make better use of their time and money to prioritize the most promising results, which improves their chances of success in later-stage studies.
Challenges of Adaptive Designs
Although it may seem like adaptive designs are an all-encompassing solution to maximize efficiency, they are not without their challenges. Most significantly, introducing changes to a clinical trial after patient randomizations begin will increase the risk of detecting misleading data trends, also known as a Type I error. This problem can be offset, but it requires implementing complex simulations and statistical techniques. Interim analyses can also open the door to bias if treatment blinding isn’t maintained properly. To avoid unblinding, interim results should not be shared with individuals involved with the conduct or management of the study. Despite the advantages, some trials are simply not suitable for an adaptive design, such as shorter programs or those with too many uncertain parameters.
How Can Studies Become Adaptive?
When sponsors are deciding whether to adopt an adaptive approach for their new clinical trial, four key questions must be considered.
- What is the study design? A study’s specific parameters will determine limitations to which modifications are most appropriate to plan for.
- How will endpoint data be collected? This places limits to when or if interim analysis is needed. If the trial is straightforward enough that patients are recruited quickly, many of them might complete their participation by the time an interim analysis can logistically be carried out.
- Is the current endpoint most appropriate for the study’s objective? Preliminary data analyses might provide more valuable results for a different endpoint that captures a trial’s treatment effect more clearly.
- What criteria must be met to change a study’s conduct? These rules must be clearly defined early on while still allowing flexibility for discussion. For example, even if statistical analysis at interim meets predetermined requirements for efficacy, potential safety signals should not be disregarded without further review.
Depending on the answers to these four questions, different types of adaptations to clinical trials can be made. Adaptive clinical trial is a vague term that can refer to prospective changes made in real-time to features such as eligibility criteria, treatment regimens for different subject groups, primary or secondary endpoints, total sample size, and more.
Although they haven’t been widely adopted yet, adaptive designs offer key advantages, such as flexibility to prospectively change planned elements of a study and more efficient use of resources. However, the reality is that this type of clinical trial can create unnecessary statistical and design complications if it is not prepared correctly. To maintain the validity and integrity of their study results, sponsors and CROs should conduct thorough planning before deciding whether an adaptive approach is the most appropriate option.