Optimizing Early Clinical Research to Accelerate Drug Development Timelines: Adaptive Study Design
Clinical Development is evolving. In the traditional paradigm, clients took a phased approach to drug development, starting with a scarce number of molecules and testing each one thoroughly, by progressing through preclinical testing, Phase I, II, and III studies. A new paradigm has emerged, whereby clients start with a larger number of candidates and work to shift attrition of these candidates to earlier in the drug development process. This approach has caused a blurring of the traditional boundaries of Phase I, II, and III studies and an emphasis on “Proof-of-Concept”. To address these challenges and achieve the objective of accurately evaluating proof-of-concept, it is necessary to innovate and approach drug development using creative and novel methodologies.
One novel approach to making better decisions faster is through the use of Adaptive Study Designs. These have been defined as “By adaptive design we refer to a clinical study design that uses accumulating data to decide how to modify aspects of the study as it continues, without undermining the validity and integrity of the trial”.1 (1Adaptive Designs in Clinical Drug Development: An Executive Summary of the PhRMA Working Group. Journal of Biopharmaceutical Statistics, 16: 275-283, 2006) Using data as it accumulates allows the researcher to adjust the study design on an ongoing basis, minimize the pursuit of unnecessary or futile investigations and optimize the design, so that critical information about the drug can be obtained and evaluated quicker. Leveraging the current regulatory acceptance of adaptive-like study designs is an ideal way to find creative ways to get the most data as early as possible for better decision making.
Applying Adaptive Study Design concepts is unique in early clinical research. Instead of using Adequate and Well Controlled studies, where the Type I error rate must be rigorously controlled, it is more common in early clinical research to use Exploratory Adaptive Clinical Studies. The study is designed from the outset to allow changes during the study based on interim examinations of data and multiple endpoints are considered in the assessment of the study results.
Among the types of Adaptive Study Designs developed at Celerion, many involve components of traditional Phase I study designs. They do however; contain additional components that allow for evaluation of multiple endpoints that traditionally would be assessed in two or more independent studies. Examples of adaptive studies designed at Celerion include
- Single Ascending Dose (SAD) or Multiple Ascending Dose (MAD) Studies with the addition of
- Food effect evaluation
- Population change (e.g., ethnic group)
- Patient cohort(s)
- Food effect and dosing regimen changes
- One or more combinations of the above
- Single Ascending Dose (SAD)/Multiple Ascending Dose (MAD) Combined Studies with or without the addition of the elements listed above
- Two-Stage Sequential Design to compare the bioavailability of two biological products
- Creative or Fusion Studies, where 2 or more traditional early clinical research studies are combined, often to better prepare for introduction into the target population. Examples include:
- Drug-Drug Interaction studies combined with evaluations of Metabolizer populations (e.g., high then low), Intrinsic factors (e.g., age, smoking), Food effect, Formulation (e.g., ER vs. IR), Dosing timing (e.g., am/pm)
- Food Effect studies combined with evaluations of meal timing, Formulation evaluations (e.g., ER vs. IR), Formulation and age group or special population effects
- Bioavailability studies combined with evaluations of food effect, dosing regimen, or dosing timing.
Evaluating the recent trends in the use of “Non-Traditional” Designs at Celerion reveals that in the 39 most recent studies, approximately half (54%) have utilized exploratory Adaptive Clinical Study techniques, while the other half (46%) are Fusion or Creative designs. Among the exploratory Adaptive Study Designs, the most common were combined SAD/MAD studies (53%), with 16% being combined SAD/MAD designs with additional components (such as a patient cohort) added. Among the Fusion/Creative designs, the most common have included adding additional components to a traditional Drug Drug Interaction study (67%) followed by fusing additional elements onto a Food Effect study (28%).
These results suggest that there are a number of creative designs currently being used by clients, to capitalize on current regulatory acceptance of such designs. While a number of considerations should be evaluated when deciding whether to employ Adaptive Study Designs in a drug development program, it is an approach that has, in our experience, delivered data faster to enable better decision making. For more information, please contact us today.