Adaptive design is a type of clinical trial methodology that incorporates prospectively planned opportunities for modification of one or more aspects of a study’s design or its hypotheses based on interim analysis of study data. Explicitly planning these pre-specified changes helps to maintain scientific integrity while also introducing greater flexibility in the clinical research environment. The major objectives of adaptive design are to make trials more efficient, informative, and likely to demonstrate significant clinical effects in investigational products. And such innovations are necessary in today’s clinical research climate where high attrition rates, lengthy research and development programs, and skyrocketing costs are common.
So far, adaptive design strategies have been especially useful for rare disease research in general and rare oncology in particular. Compared to conventional study designs, the savvy application of adaptive trial design may:
1. More efficiently provide the same information as conventional methodologies.
All key stakeholders involved benefit from increased efficiency in clinical trials:
- Patients are more likely to receive effective treatment over the course of the trial. Changes to treatment arms often allocate more subjects to superior treatment regimens and minimize the number of subjects exposed to either ineffective or toxic doses.
- Sponsors may have lower development costs for their product, as they may run fewer discrete trials.
- Researchers are more likely to produce clinically relevant publishable results.
- Regulatory agencies might have fewer protocols and applications to review overall with less redundancy.
Many adaptive design proponents argue that these strategies represent the best use of limited funding. At the most basic level, such cost-saving elements may include early trial termination when an investigational drug does not appear beneficial or, on the other hand, is extremely effective. Adaptive design may also include sample size re-estimation where reassessment and adjustment of the sample size minimizes the likelihood of a trial failing due to lack of statistical power.
However, it’s important to keep in mind that adaptive design is top heavy: these designs require a lot more effort early on but have the potential to reduce overall costs further down the road. However, realizing such savings requires intelligent application: not all clinical trial situations will benefit from adaptive design.
2. Improve clinical trial efficacy.
Adaptive design can increase the likelihood of achieving the study objective, especially with the small sample sizes found in rare disease research. As such, the FDA’s Critical Path Initiative for driving innovation in regulated product development has identified adaptive design as a way to improve clinical trial efficacy at all stages of development.
3. Yield an improved understanding of the investigational product’s effects.
Adaptive design trials can yield more robust preliminary data, giving researchers more comprehensive information on dose–response relationships and differences between subgroups. One contributor to this effect may be that the circumstances of these trials can be more similar to the actual clinical setting where these products would be put into regular use compared to conventional studies.
4. Better align today’s human subject research with core ethical principles.
In 1978, the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research issued the Belmont Report. This document identified three core principles for clinical research ethics: respect for persons, beneficence, and justice. In study design, the three primary applications of these principles are informed consent, assessment of risks and benefits, and selection of subjects.
Certain types of adaptive study design help researchers to better observe the basic ethical principles of research in human subjects, such as strategies that decrease the likelihood of patients being randomized into ineffective treatment arms. But, while adaptive designs may address some ethical considerations, they also, unfortunately, have the potential to create new ones.