Adaptive Clinical Trials Design – Part II

Moderator’s Note: Please if you have questions or clarification to be made about Adaptive clinical Trial design, please do note we have the author of this piece online who will be ready to give further details and answer all questions. The part I of this posting was posted earlier. We hope to send in a three more postings to help us all understand this evolving concept for HIV prevention research. Happy reading.

In the clinical trials realm, Adaptive Clinical Trial Design (ACTD) is a clinical trial methodology that is rapidly gaining popularity and acceptance.  The primary reason for this phenomenon is due to the increasing cost of operating clinical trials which is often the by-product/causality of high failure rates of clinical trials.  ACTD has many advantages to facilitate the effectiveness of clinical trial operations.  However, as a relatively new methodology, it does have its challenges as well.

In this segment of our three-part article on Adaptive Clinical Trial Designs, we will (1) provide an overview on what ACTD is, (2) describe how it differs from the standard clinical trials designs, and (3) briefly highlight some of the advantages and disadvantages of ACTD.   In subsequent articles, we will (1) describe in greater details the pros/cons of ACTD, (2) describe regulatory authorities perspective and guidance on the topic and (3) offer recommendations on how to implement ACTD.

So, what exactly is Adaptive Clinical Trial Designs?  In accordance to the 2010 FDA Guidance for the industry on “Adaptive Design Clinical Trials for Drugs and Biologics,â€� an adaptive design clinical study is defined as:

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 (usually interim data) from subjects in the study.  Analyses of the accumulating study data are performed at prospectively planned time points within the study, can be performed in a fully blinded manner or in an un-blinded manner, and can occur with or without formal statistical hypothesis testing.

It has been argued by some that researchers do routinely modify clinical studies during the course of the studies via aProtocol Amendment� or Protocol Modification.� Modification in clinical trials may include administrative changes, early trial termination, addition/removal of treatment arms, changes in trial sample population size, and treatment arm allocation regimen.  How so, does this then differentiate ACTD from standard or conventional clinical trial designs?

There are two operative terms in the above definition for adaptive studies:  prospectively and modification.   Conventional clinical trial designs often use fixed or pre-determined sample sizes that do not use adaptive elements.  In other words, with ACTD, anticipated changes are planned before the study commences and adjusted accordingly.  On the other hand, with conventional studies, changes/amendments are allowed to be made after the commencement of a study for safety or administrative reasons if they do not impact the integrity of the data collected or statistically alter the initial statistical design or hypothesis of the study.

As described in the aforementioned FDA Guidance on Adaptive Design Clinical Trials, the three main advantages for adaptive clinical trials are that it:

•         Allow studies to be operated more efficiently and provides the same information

•         Increases the likelihood of success on the study objective

•         Yields improved understanding of the treatment’s effect (e.g., better estimates of the dose-response relationship or subgroup effects, which may also lead to more efficient subsequent studies).

The advantages, however, need to be cautiously weighed with the increase likelihood of introducing study bias with a poorly designed or poorly implemented adaptive methodology.  This is a major disadvantage and concern that is shared by regulatory authorities such as the FDA, drug developers, and the end users (i.e., customers).

As previously mentioned, this is simply a brief introduction to adaptive clinical trials methodology.  Additional details will be provided in subsequently articles.  However, for those eager to immediately learn more about Adaptive Clinical Trials Designs, below are three recommended readings:

1. Guidance for Industry . Adaptive Design Clinical Trials for Drugs & Biologics.  US Department of Health and Human Services; Food and Drug Administration.  February 2010.

2. The Agile Approach to Adaptive Research.  Written by Michael Rosenberg.  Published by John Wiley & Sons, February 2010.

3. Adaptive Clinical Trials: The Promise and the Caution.  Written by Donald Berry.  Published in Journal of Clinical Oncology, December 2010.