Eyes Wide Open

Adaptive clinical trials, resulting in more rapid approval of safe and effective drugs and biologics, promises to open doors to available scientific advantages. The focus of this type of design is on finding early positive safety and efficacy signals, utilized for implementing "adaptive" changes in trials to shorten the time for new treatments to get to market.

George Mills, MD

Is the industry ready to implement adaptive trial design? We are ready to discuss, define, and implement exploratory trials that incorporate adaptive features. In this evolving process, the industry needs to be cognizant of adaptive trial design complexity and careful and conservative in the approach until there is collective knowledge and experience.

Adaptive clinical trial design will first emerge in early phase studies. Clinical study sponsors, contract service providers, and regulatory authorities will need to learn about implementing this type of trial design in Phase I and Phase II first within the Investigational New Drug (IND), and then, based on the learned experiences, features of adaptive design will be incorporated in the New Drug Application (NDA)/Biological License Application (BLA) Phase III clinical trials.

Key implementation challenges facing the industry include the following:

Making interim decisions. Good decisions will be based on ensuring that there are the right data available to implement a change in the trial. These decisions will focus on conducting the adapted study with an enriched or sub population going forward in the clinical development process.

Planning and conducting adaptive clinical trials. Adaptive clinical trials will be extremely complex studies due to critical, rapid shifts required and the necessity for detection of early safety and efficacy signals. There must be a rapid response process for assessment and agreement among the sponsor, contract service provider, clinical sites, and regulatory authority to enable adaptation of the trial design.

Ensuring both data integrity and unblinding. A concern will be overemphasizing early observations with adaptations, which may introduce bias and result in potential data unblinding. To address these issues, the industry may need to introduce an independent Data Monitoring Committee to maintain and protect the integrity of the blind.

Putting a regulatory structure in place for adaptive trials. With the potential rapid changes in clinical trials, there may be multiple amendments sent into regulatory authorities. The regulatory structure must be able to receive and respond to amendments and assure that they conform to the prospectively planned protocol design.

With adaptive trial design being an important part of the FDA Critical Path Initiative, open meetings between the FDA and sponsor groups, which have included developing a set of adaptive design tools for early, exploratory trial design/INDs, have moved the industry closer to implementing adaptive design features. Furthermore, the industry will need to adopt early design tools since the speed of information and detection of signals—enabled by technology, such as imaging results—will be critical to implement adaptive trial design.

As the industry works together on adaptive design features for early phase trials, the goal is to separate the promising from the not-so-promising drugs/biologics. What we may see first is implementation of a narrower scope approach. If adaptive clinical trials are to be implemented across the full range, we may begin with limited features in what could be called innovative clinical trial design, which requires a new structure, technology solutions, a range of clinical development expertise, and regulatory experience.

Ultimately, as the industry must enable new scientific advances, it should move forward with an iterative approach to implementing adaptive designs, while gaining the necessary complete safety and efficacy information.

George Mills, MD, is vice president, medical imaging consulting, for Perceptive Informatics, a PAREXEL company.