What is a Dose Escalation Design?

A dose escalation design study is a type of trial used early in drug development that begins with a low dose of the treatment and slowly gives participants stronger doses to attempt to find the maximum tolerated dose. There are numerous types of dose escalation designs, such as 3+3 and accelerated titration. These designs are used to determine the safety and efficacy of different doses of the intervention.

What is a 3+3 Design?

A form of dose escalation design that is somewhat common in Phase I trials for oncology. First, 3 participants are given a low dose of the experimental treatment and monitored for pre-specified toxicity events. If 0 participants experience one of these toxicity events, then the next group of 3 participants is enrolled at a higher dose. If 2 or 3 participants experience toxicity, then the next group of 3 participants is enrolled at a lower dose (or the study ends). If 1 participant experiences toxicity, another group of 3 participants is enrolled at the same dose (hence the name, 3+3): if 1 or more of those participants experience toxicity, then the dose is lowered for the next group of the study ends. Otherwise, if 0 of the additional participants experience toxicity, the next group is enrolled at a higher dose.

3+3 designs are often used because of their fairly early-to-follow approach to dose escalation—investigators or clinicians can follow a simple flowchart for how each cohort of 3 participants should be enrolled, without the need for random assignment or computer algorithms. Research has shown, however, that 3+3 designs do not accurately determine the maximum tolerated dosage in many circumstances, and that other, modified designs (such as accelerated titration) are more effective.

Further Reading:
https://ascopubs.org/doi/full/10.1200/EDBK_319783

What is an Accelerated Titration Design?

An accelerated titration design study is a form of dose escalation study design that is used in Phase I, often in oncology; these trial designs aim to fulfill a similar goal as 3+3 designs (finding the maximum tolerated dose), but in a more efficient manner that results in fewer participants receiving sub-therapeutic doses of treatment. Accelerated titration designs vary significantly but tend to emphasize a more aggressive approach to the early portion of the study when participants are on lower doses. These designs appear to better balance the detection of the maximum tolerated dose with the efficiency of the study design and may result in fewer participants being under-treated.

Example: One kind of accelerated titration design enrolls only one participant at each dosage until the first toxicity event, at which point larger cohort sizes may be used to examine that dosage and higher doses to determine safety. Accelerated titration designs may also allow for intrapatient dose escalation, where a participant on a lower dose may be escalated to a higher dose if no toxicity is observed.

What are Adaptive Trials or Adaptive by Design?

Adaptive by design studies are a type of trial that allows for modifications to be made to the study design, such as the sample size or dosages or even which interventions are being used, based on the results of the study. These kinds of designs are used to increase the efficiency and power of the study. Adaptive trials are dynamic and flexible due to allowing modifications to be made based on interim or ongoing results. These designs enable researchers to refine their hypotheses and study protocols in response to accumulating data. Adaptive trials can maximize efficiency, reduce costs, and accelerate the development of new treatments by adapting to emerging evidence.

By building adaptiveness into the study design from the beginning, studies maximize data-gathering and minimize resource costs. Adaptive by design techniques may have interim analyses to confirm sample size estimates, opportunities to remove treatment arms that are performing suboptimally, the ability to seamlessly transition from one clinical development phase to another, or computer models that are used in dose-finding to determine each subsequent dose based on the efficacy and toxicity of previous doses. Adaptive designs need to be carefully designed to maximize their potential while ensuring participant safety and adherence to regulatory guidance.

Benefits of Adaptive Designs include:
Although adaptive designs are more complex, investing in them can offer many potential benefits including:

• Increasing the trial’s probability of successfully detecting a treatment difference
• Faster “go/no-go” decisions (stopping trials for ineffective or unsafe drugs more quickly)
• Reducing the overall time and cost of the trial
• Reducing required resources
• Better dosing and frequency decisions
• Reducing time to market
• Increasing efficiencies
• Delivering the right drug to the right patients, improving patient safety

Further Reading:
https://alimentivstatistics.com/why-arent-more-clinical-trials-using-adaptive-designs/
https://www.alimentivstatistics.com/clinical-trial-cro-services/clinical-trial-design-services/adaptive-trial-design/

FDA guidance on adaptive designs:
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/adaptive-design-clinical-trials-drugs-and-biologics-guidance-industry

What is a Basket Study Design?

A type of study design most commonly used for cancer treatments. In a basket design, a single treatment is used for several different cohorts (“baskets”) of participants with different but related diseases or conditions, such as. differing types of cancer with the same mutation. These designs are useful in determining whether a treatment appears to function across variations in a disease or whether there are specific subgroups that experience the greatest or least treatment effect.

What is an Umbrella Study Design?

Umbrella designs can be viewed as a counterpart of basket designs. In an umbrella design, participants all have variations of the same disease, such as a single type of cancer with multiple mutations, and are given different treatments/interventions based on the variant. This design may also be applied based on predictive risk factors in addition to/other than disease variants. Umbrella designs allow for efficient testing of multiple treatments in patients with specific genetic mutations.

What is a Platform Study Design?

A platform study design is a type of trial that uses a common infrastructure and patient population to test multiple interventions simultaneously against a common control group. This design allows for the efficient testing of multiple interventions and the sharing of resources. Platform trials are carefully designed with pre-specified rules for adaptation to allow for the addition of new arms, removal of ineffective or undesirable arms, and multiple interim analyses or data looks. These trials are often designed to continue for a long or indefinite period. May also be referred to as Multi-Arm Multi-Stage (MAMS) designs.

Final thoughts

In part 3 of a 4-part series on the different types of clinical trial designs, we continue to explore how a variety of clinical trial designs can be used to generate reliable evidence about the safety and efficacy of new treatments.

As previously stated, the selection of a trial design should be based on the specific research objectives, the nature of the intervention being tested, the target population, available resources, and ethical considerations. Since each design has its unique features and considerations, study design decisions should be made collaboratively using input from trial stakeholders, subject matter experts, and statistical experts to not only understand the strengths and limitations of each but to also ensure that the chosen design is the best fit for the goals of the study.

As medical knowledge advances, researchers need to continue exploring innovative trial designs that adapt to emerging evidence, maximize efficiency and ultimately lead to improvements in overall patient care.