At PAREXEL, we frequently get asked questions about protocol optimization – what it is, how it works, and trends in…
Today, we see more and more clinical trials with adaptive design protocols. Part of my job is to evaluate a need and determine the advantages and benefits for implementing an adaptive design for our clients and, ultimately, for a patient in need of the medicines being developed.
Stepping back, it is important to understand what adaptive design trials are, and there are several definitions. The one that I like most and prefer to use is the definition proposed in the FDA draft guidance document issued in 2010. It defines an adaptive trial as a study that includes a prospectively planned opportunity for modification of one or more of the specified aspects of the study design and hypotheses based on the analysis of data. The challenge here is to modify these elements without jeopardizing the validity and the integrity of the study data.
An analogy I like to use is to think of the traditional way we conduct clinical trials as somewhat analogous to a cargo plane without windows; in other words there is no way from the outside to tell what is going on inside the plane while the plane is flying to its destination and we typically have to wait until the plane lands before we are able to look into the plane. The analogy of course is that in a traditional trial you need to wait until the end of the study to lock the database before we get a sense of what happened during the study. An adaptive trial is more like a passenger plane with windows – in other words, you have these opportunities / windows during the course of the trial to look at and evaluate the data and make some predefined changes or course adjustments. Examples of adaptive trial designs include: Designs where you stop the trial or an arm because the treatment or dose is not working; sample size re-estimation where we modify incorrect assumptions on effect size and population variance and seamless Phase I/II or Phase II/III trials where we combine studies in order to save time and cost.
It is also important to recognize that there are differences between adaptive trials and traditional trials – and thus some different requirements. I like to think about adaptive trials as traditional trials on steroids. These trials utilize a more revolutionary than evolutionary approach compared to traditional trials. Likewise, they also utilize a more iterative as opposed to the traditional linear approach. But the advantages of an adaptive trial come at a cost – the operational infrastructure required to execute an adaptive trial is more complex. These complexities increase when the design calls for unblinding the data. In this case, you need to take special precautions to guard against the inadvertent release of data to unauthorized individuals which could potential invalidate the results of your trial. A key requirement is to modify study elements without undermining the validity and integrity of the study. Validity refers to the requirement to avoid any form of statistical bias in the study and integrity refers to the need to minimize operational bias. So, in addition to very specialized statistical experience, these trials also require an experienced cross-functional and integrated operational approach. Very importantly, these trials also require a technology infrastructure or environment that enables real-time decision making and implementation.
Recently, there has been an increased interest in adaptive trial design. There are several reasons for this increased interest. For one, the regulatory agencies -- especially the FDA in the U.S. and EMA in Europe -- are emphasizing the use of adaptive trials. Both of these agencies have been very supportive in terms of their comments around the use of the adaptive designs where the designs are appropriate. Secondly, the pharmaceutical industry is facing major pipeline and financial challenges, and we are therefore searching for ways to reduce the cost and time associated with clinical trials - adaptive trials offer a possibility in this regard. Thirdly, there have been several recent advancements in the adaptive design and operational execution enablers - that is advancements in the development of the appropriate operational execution environment to run these trials, including statistical and information technology advances that support these trials. And then finally, there is a growing interest in personalized and targeted medicines and master protocols -- adaptive designs align very well with both of these two concepts.
PAREXEL is one of the leaders in adaptive trials. In particular, many of the technologies developed by our PAREXEL Informatics division are widely used – PAREXEL Informatics has been involved in more than 100 adaptive trials. Adaptive trials are a key focus area at PAREXEL, and we continue to invest in both our technologies and their further development, and, more importantly, in our operational execution environment and processes for running these studies. If you are considering running a clinical trial with an adaptive design, we would welcome the chance to talk to you about your specific needs and how PAREXEL can help.
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Dr. Sy Pretorius, Chief Scientific Officer, talks about advances in Adaptive Design Trials Click here.