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Adaptive Trial Design in Clinical Trials- What You Need to Know: Part 1

Adaptive Trial Design in Clinical Trials- What You Need to Know: Part 1
14 November 2016

By: Dr. Greg Wei, Statistical Research Fellow

Even as spending in biomedical research has surged, the pace of successful pharmaceutical development has slowed. This has motivated the development of innovative adaptive designs (AD) in clinical trials. AD trials take advantage of accumulating information, enabling modifications after a trial has commenced. Adaptive designs reduce both time and cost, and help determine the best dose as well as the appropriate patient populations for which a drug may be efficacious.

As defined by FDA Guidelines, adaptive design is:

A study that includes a prospectively planned opportunity for modification of one or more specified aspects of the study design and hypotheses based on analysis of data (usual interim data) from subjects in the study. Analyses of the accumulating study data are performed at prospectively planned timepoints within the study, can be performed in a fully blinded manner or in an unblinded manner, and can occur with or without formal statistical hypothesis testing.

While adaptive design is a fairly young concept, the Food and Drug Administration (FDA), the European Medicines Agency (EMEA), and the pharmaceutical industry have responded positively, developing guidelines and encouraging the use of this innovation.

Types of adaptive designs

It is important that the trial protocol is set prior to initiation of the trial, even in an adaptive trial design. The adaptation process may continue throughout the trial, as previously pre-set by the protocol. Modifications made may include dosage, sample size, patient selection criteria and sometimes, even the formulation of the drug undergoing trial or its mix with companion drugs.

Trial adaptations can incorporate a number of designs, including the following:

  • Adaptive randomization: With this design, we can alter the ratio between placebo and treatment. This approach enables us to make the study more efficient.
  • Group sequential: Interim analyses allows the sponsor to stop the trial.
  • Sample size re-estimation: Enables a change in sample size based on blind or unblinded interim analysis.
  • Drop-the-loser design: Two stage design that drops inferior specified patient groups, or arms.
  • Adaptive dose finding design: Accomplished through continuous assessment (CRM) and Bayesian methodology.
  • Biomarker adaptive design: Allows design adaptation based on patient biomarkers.
  • Adaptive treatment - switch design: Treatment is switched due to efficacy or safety.
  • Adaptive hypotheses design: Examples include switching from a superiority hypothesis to a non-inferiority hypothesis and between the primary study endpoint and secondary endpoints.
  • Adaptive seamless phase II/III design: No pause when Phase II transitions into a Phase III trial.
  • Multiple adaptive design: A combination of designs.

Why we need adaptive designs

Adaptive designs speed up new drug development and overcome the limitations of FIXED, or quantitative, designs. Earlier decisions can be made in terms of saving patient exposure and resources as well as for conditional new drug application (NDA) filing. Optimal treatment dose and patient population can be determined. Adaptive designs assist in developing personalized medicine to deliver superior efficacy and reduce adverse events (AE).

Cautionary tales – What clients need to know

While adaptive designs can speed up clinical trials and help put new drugs on the market faster, they do come with caveats and precautions. Balance is of supreme importance, where flexibility and efficiency are on equal footing with validity, integrity and interpretability, with neither sacrificed. Adaptation must not alter the quality of the trial.

A Type I error (incorrect rejection, or false positive) should be preserved and observed, especially in Phase III trials. A data monitoring committee (DMC) is necessary to maintain the trial’s validity. Trial feasibility should be carefully evaluated to ensure that patients most appropriate for the study are recruited.

What Adaptive Designs Are Not

Just as important as the reasons for using adaptive designs, they should not be used to meet certain ends. For example, adaptive designs are not used for real time data review; while studies go through a lot of review for safety, that is not the purpose of AD. Adaptive design cannot be used to bury the reality of a poor study. If the recruitment is faulty, the trial drug is not effective or the patients do not comply with the requirements, an adaptive design trial will not provide valid results. The data is not meant to be looked at out of mere curiosity or pressure by the company board. Ultimately, adaptive design clinical trials must maintain the same integrity and validity as other trials and not be seen as cheap, quick and dirty studies.

Why A DMC Is Needed

Adaptive design clinical trials require a data monitoring committee as a set of eyes separate from those conducting the studies. The DMC is responsible for monitoring for safety and for interim analysis of efficacy during Phase III trials. A DMC can be valuable in key Phase II trials as well. An independent statistical analysis center (SAC) is required to produce materials for review by the DMC.

Part 2 – Next Week!

Come back next week for Part 2 to learn about adaptive trial design for early clinical trials, FIXED late phase and seamless Phase II/III.

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