Adaptive Trial Designs
Flexibility of Adaptive Early Phase Study Designs
Sabina Paglialunga, PhD Director, Scientific Affairs
Adaptive clinical trials are characterized by innovative and flexible designs that incorporate safety and other information acquired during a study to instruct the next steps in a trial. Typically, these pre-planned adjustments include sample size refinement, subsequent dose level selection, or allocation ratio. In the case of patient studies, adaptive elements may consist of inclusion/exclusion criteria adjustment or stopping rules based on success or lack of efficacy . Adaptive study designs are well established for cancer trials , and while they are applied to a lesser degree in other indications, a limited search in ClinTrials.gov revealed nearly 95 non-oncology industry sponsored adaptive trials over the past decade.
Regulatory Perspective on Adaptive Designs
As interest in flexible design elements grows across all indications, both the FDA and EMA have issued updated guidance on adaptive trial designs for drugs and biologics in recent years [3, 4]. For early phase exploratory studies, the FDA touts the advantages of an adaptive design that advises dosing, pharmacokinetic (PK) and pharmacodynamic (PD) responses, which may improve the design and possibly the chances of success of later-phase trials .
Adaptive Early Clinical Trial Designs
For single ascending dose (SAD) and multiple ascending dose (MAD) studies, adaptive design elements can be incorporated into the study protocol to add flexibility. This can be a valuable approach when there are still many unknowns in the initial clinical drug development phases. Case examples of recent adaptive protocols are highlighted in Table 1. These elements, such as alterations to drug dose, number of cohorts, or schedules of PK sampling and PD assessments, must be pre-specified in the protocol. For each adaptable component, limits should be set to address any safety concerns and to operate within acceptable risk parameters . For example, if a blood sample schedule can be adjusted to optimize evaluable PK or PD data, the maximum number of blood draws should be noted in the protocol and not exceeded.
Table 1. Case Studies of Early Clinical Trial Adaptive Study Designs
|Case Study||Study Design||Adaptive Elements||Implementation|
|Adaptive Dose and PK||2-part SAD and MAD study in healthy volunteers||Drug dose, infusion volume and/or rate, PK schedule (time points and number of samples)||Adaptive elements were modified based on AEs, clinical finding, safety and tolerability resultsProtocol allowed for reduced PK sample number if data permitted|
|Adaptive Cohort Number||SAD study in healthy volunteers||Cohort number and dose levels defined for groups 1-5 Option to add up to 2 additional cohorts||Upon review of cohort 1-5 safety and PK data, the decision will be taken to continue with increased dose levels, or an intermediate dose, or to cancel cohorts 6-7|
|Adaptive PD Response||MAD study in participants with obesity||Number of PD assessments||Multiple PD assessments evaluated in cohort 1 with option to omit or adjust PD schedule in subsequent cohorts Protocol also indicated the maximum number of PD assessments that can be taken|
|Adaptive Sample Size||Fixed-dose combination vs free dose cross-over bioequivalence (BE) study in healthy volunteers||Sample size re-estimation Clinical study activity paused during COVID-19 pandemic before all participants completed cross-over scheme||Adaptive and interim analysis was performed to re-evaluate study sample size and power, using a validated method for crossover BE design . Trial results demonstrated BE based on completed participant data |
Advantages of Adaptive Early Clinical Trials
With pre-defined adaptive protocol elements, no amendments are required, which can save time and result in scheduling efficiencies. In the case of future pandemic outbreaks or other extraordinary situations, adaptive designs can serve as a mitigation step and potentially ‘save’ a study from timely delays or the need to repeat the trial. This approach was applied in a BE study, where sample size was re-assessed midway through trial conduct using validated statistical methods to complete the trial without further interruption from a COVID-19 outbreak . Ultimately, the advantage of adaptive, early clinical trial designs can lead to both time and costs savings. Celerion’s Protocol Design and Development Scientists are trial experts and can design early clinical trials with flexible and adaptive elements to get the most out of a study, for less.
1. Pallmann P et al. BMC Med. 2018;16(1):29.
2. Bothwell LE et al. BMJ Open. 2018;8(2):e018320.
3. Food and Drug Administration. Adaptive Designs for Clinical Trials of Drugs and Biologics Guidance for Industry. 2019. https://www.fda.gov/media/78495/download.
4. European Medicines Agency. Adaptive Pathways. https://www.ema.europa.eu/en/human-regulatory/research-development/adaptive-pathways
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6. Potvin D et al. Pharm Stat. 2008;7(4):245-62.
7. Csonka D et al. Pharmacol Res Perspect. 2021;9(5):e00846.