Adaptive Trial Design

According to US FDA, adaptive designs are studies that “include a prospectively planned opportunity for modification of one or more specified aspects of the study design and hypotheses based on analysis of data (usually interim data) from subjects in the study”. “Prospective” in this definition means that possible modifications are specified before the data are examined in an unblinded manner.

The main idea behind adaptive trials is to lessen the unpredictability and inherent risks in clinical development by gathering additional information from the ongoing trial and using these information for better conduct of trial.

Adaptive design provides opportunity to gather more complete information about the drug and its dosage through interim analysis which helps in reducing the chance of phase III (confirmatory) trials being toxic/inefficient and thus increases the chance of success of phase III. This design can be a time saver as it may accelerate the process of approval for marketing by providing clear information about drug efficacy, drug dosage etc. Therefore, this design can be helpful for drug developers in terms of economy and for patients in terms of health (i.e., getting improved and required treatment and avoiding unnecessary exposure to the ineffective treatment).

Thus, an adaptive trial design is a design that permits changes to the trial and/or statistical procedures of the trial after its commencement without reducing its validity and integrity. This design is also known as “flexible design” because it carries flexibility in its operation.

Example – In a particular clinical trial, the researcher estimates that increasing the sample size more than recommended in research can render the result in efficient manner. Now if this particular trial follows adaptive trial design instead of traditional trial design, then the researcher can implement modifications in the trial design to achieve the optimum result.

Strengths of Adaptive trial design
  • Helpful in reducing the number of study subjects (wherever possible) and thereby reducing the utilization of resources in a trial
  • Flexible in nature
  • More efficient
  • Cost effective
  • More likely to detect a treatment effect when one exists
Weaknesses of Adaptive trial design
  • Complex in nature due to intermittent changes
  • Operational challenges due to flexibility in design
  • Risk of creating inefficiencies if poorly planned

Requirements for successful implementation of Adaptive trial design

Adaptive trials design does analysis of the collected clinical data and introduces adjustments which can result in improving the statistical power throughout the course of the trial. This design can be utilized in both early (exploratory) phase and late (confirmatory) phase. However, rigorous risk-benefit assessment is required to assure that the potential scientific and ethical gains outweigh the risks of causing bias or trial inefficiencies. When researcher identifies that changes in running trial can provide optimum result then, it will be wise decision to introduce changes. The required stuff to introduce adaptive trial design are as follows:

  • Interactive infrastructure for fast communication across trial sites and with the data monitoring committee about the implemented changes
  • Robust observation system
  • Flexible drug supply process
  • Advanced statistical process for analysis of changes made during the trial, etc.

A Bayesian statistical approach is known to be well befitted for adaptive trials as this approach permits the automatic updates of new information as it becomes available.

Adaptive trial  Vs. Traditional Randomized Controlled Trial (RCT)

In case of traditional RCT, study subjects (human beings) are allocated to control and investigational  group through randomization process and it is followed throughout the trial. Whereas, in adaptive trial, patient outcomes are observed and analysed at predefined interim points and predetermined modifications to study design can be implemented based on these observations.

In traditional trial design, analysis is done once the trial is completed but in adaptive trial design, interim analysis is done to understand the trial future and to make necessary modifications for optimum results. These changes may include total sample size, allocation ratio, eligibility criteria, addition/reduction in treatment arm, etc. Adaptive designs have been developed as an alternative to traditional RCT design.

Categories of Adaptive trial design

Types of Adaptive trial design