Phase 2/3 adaptive trials designs provide more flexibility, allowing a study to be modified in light of emerging data.

What is an adaptive trial?

The conduct of a trial and plans for data analysis are defined in a clinical trial protocol. No significant deviation from this plan is allowed without a protocol amendment, which must be approved by regulatory authorities. An adaptive trial builds in more flexibility by outlining ways that a study might be modified, without undermining the validity and integrity of the study, in light of data obtained.

Decision rules – what changes can be made, under what circumstances and when – must be defined in advance, and any adaptation must be based only on data generated in the study.

A trial using an adaptive design may be more efficient and less costly than separate phase 1 and 2 studies. However, extensive planning and pre-definition of decision rules is required, alongside planned interim data analyses.

What kind of adaptations can be considered?

There are a range of possible adaptations:

  • Interim adjustment of sample size to ensure sufficient statistical power.
  • Halting of a study due to demonstration of efficacy or lack of efficacy.
  • Dropping of an inferior study arm.
  • Changing the allocation ratio so more patients are likely to receive a superior therapy.
  • Changing eligibility criteria to narrow the scope of the study or transition from phase 2 to phase 3, when more patients are recruited.

Adaptive studies are also used to compare a range of different treatments. If interim data analyses may that particular treatments are ineffective, or less effective than others, use of these treatments can be halted.

Advantages of an adaptive trial design: Such trials are often more efficient, informative and ethical than trials with a traditional fixed design, since they often make better use of resources (time and money) and might require fewer participants.

Disadvantages of an adaptive trial design: They require extensive planning and statistical simulations during trial preparation and do not always result in increased efficiency, lower costs or shorter study duration. They require additional interim data analyses and possibly the use of advanced statistical methods.

How are adaptations managed?

In general, interim data analyses time points are set out in the original trial design. Specific criteria are included that dictate (a) whether a trial continues as before or is modified and (b) how it should be modified if changes are necessary.

Interim data analyses are usually carried out by an independent drug safety and monitoring board, which is able to unblind study data if necessary.

If the interim analysis shows the study has met prespecified criteria, the remainder of the study goes forward. If not, usually, the study arm concerned is halted or abandoned. All this is pre-specified in the original statistical design.

Further information and additional resources

FDA guidance on phase 2/3 adaptive trial design