Adaptive Dose-finding Design

In a traditional design, all the key parameters are pre-specified and they will be constant throughout the trial. This may lead to a trial which may produce ineffective outcome even if the treatment is actually effective. Generally, when a trial is designed, there are number of factors which are not certain (e.g., uncertainty in optimal dose, correct sample size, etc.) with respect to the best way to treat study subjects.

Adaptive designs can be helpful in minimizing/eliminating these uncertainties. Adaptive designs work on accruing data and allows changes in the key parameters (if required for the improved outcome) according to pre-specified rules. In case of adaptive design, once the study begins, data is collected at interim points. This analysed information can help in reducing the uncertainties regarding optimal treatment approaches.

An adaptive dose-finding design is one of the types of adaptive design. Adaptive dose-finding design is often used in early-phase clinical development in order to find out the minimum effective dose and the maximum tolerable dose, which in turn helps in establishing the dose level for the next phase trials. In general, these studies are conducted to study the effect of different doses levels of a product on a response of interest.

The objective of this design is to check if one or more doses of an investigational drug can provide superior efficacy in comparison to standard treatment while maintaining an acceptable safety profile.

This design identifies multiple doses within a certain range. However, the number of dose groups may reduce during the trial process. Interim analysis of accruing data related to safety and efficacy decides which dose should continue and which dose should stop. Generally, doses which do not provide any information or which meets the category of inappropriateness are refuted during these analyses. On the other hand, these designs may suggest to add more preferable doses also. Thus, any new participant who gets enrolled post analysis receives the doses according to the responses of the previous participants. This step helps in enrolling more participant in a dose regime which may elicit more meaningful data.

In general, CRM (Continual Re-assessment Method) is used in combination with the Bayesian approach to study the adaptive dose-finding design.

Advantages of Adaptive dose-finding design

  • Drop of inferior dose groups early
  • Possibilities of modification of dose groups 
  • Enhances the chances of correctly identifying the Maximum Tolerable Dose (MTD) with limited number of subjects 
  • Ethically beneficial design as less patients exposed to unknown doses

Disadvantages of Adaptive dose-finding design

  • Correct selection of dose range for the study
  • Chances of dropping promising dose groups