Adaptive clinical trial design

Introduction: What are adaptive design clinical trials?

Adaptive clinical trial design refers to a particular clinical trial design wherein changes to one or more aspects of the protocol are permitted or planned over the course of the study, in response to incoming subject data or results.[1] Adaptive trials are an evolving type of clinical trial that can, in some cases, offer ethical or statistical benefits over the more-common alternative, fixed-design clinical trials.

In this outline, we discuss the key concepts underlying adaptive design clinical trials, including the history of adaptive trials, their unique design components, potential benefits of adaptive clinical trials over their fixed counterpart, guidance on adaptive clinical trial design and best practices, and potential challenges that could be encountered.

A brief history of adaptive design clinical trials

Adaptive design clinical trials marked a significant evolution in the conduct of clinical research. They emerged as a response to the often rigid, traditional approach to trial design, which often led to unnecessary delays and unproductive utilization of resources when certain unexpected challenges arose. The roots of adaptive design trials can be traced back to the 1970s, with pioneering work by researchers such as Zelen and Wei. Years later, in the late 1990s and early 2000s, interest in adaptive designs started growing rapidly. This surge in popularity followed efforts by researchers like Thomas Burnett who introduced sequential methodologies into mainstream medical statistics, and simultaneously, Bayesian methodologies further augmented the statistical toolkit of clinical statisticians, enabling more flexibility in clinical trial design and analysis frameworks. Official guidelines for adaptive trial design from regulatory bodies like the Food and Drug Administration (FDA) in 2010 and the European Medicines Agency (EMA) also played a fundamental role in broadening the acceptance and usage of these innovative designs.

Fixed vs adaptive clinical trial design

Fixed and adaptive clinical trials represent two different broad approaches to conducting clinical studies. In a fixed design, the key features of the trial—such as the randomization assignment protocol and endpoints—are set at the start of the study and remain unaltered throughout. This rigidity allows for simpler and clearer trial operation, but limits flexibility in terms of responding to emerging data trends as the study proceeds.

That is precisely where adaptive clinical trial design offers benefits; it allows changes or adaptations to be made as the trial progresses, based on interim results and emerging data. While this flexibility can potentially optimize the detection of any effects of the study drug, the assessment of its safety, and even protect participant well-being, adaptive study design implies more complex protocols and statistical analysis. Follow along as we explore adaptive clinical trial design in more detail.

Components of adaptive trial design

In order for it to be feasible to make modifications during the course of the study, there are several key design components that are essential for successful adaptive clinical trials.

Thorough planning and a clear trial protocol

In the planning phase of any trial, researchers must carefully consider the specific objectives of their study and develop a detailed protocol that outlines exactly how the trial will be conducted. In adaptive design trials, the study protocol must clearly lay out the conditions for the adaptations and specify the precise ways in which the changes are to be made during the study.

Intentional monitoring and analysis

A crucial component in adaptive design clinical trials is the continuous monitoring and analysis of incoming study data. In order to make informed decisions about adaptations to the trial protocol, investigators will likely conduct interim analyses at predefined points. As the results of these preliminary findings are analyzed in relation to predefined endpoints or outcomes, a given aspect of the trial can be adjusted accordingly.

Modifications

The ability to modify one or more aspects of a clinical trial in response to emerging data is one of the defining features of adaptive trial design. These modifications could include changes to patient enrollment criteria, treatment regimens, or randomization/allocation schedules. The conditions for the modifications are laid out in detail, including when the changes are to be made and under what circumstances. Such adaptations do not form part of a typical fixed design clinical trial.

Benefits of adaptive clinical trials

Adaptive clinical trials offer several advantages over traditional fixed designs, but may not always be feasible or tangibly beneficial. Nonetheless, the potential benefits described below have led many pharmaceutical companies and researchers to embrace this innovative approach.

1. Improved efficiency

By allowing modifications based on early/interim data analyses, adaptive trials can save researchers time by identifying drug effects or ineffective treatments with smaller sample sizes and/or over a shorter duration, freeing up and redirecting resources to focus on more promising avenues.[2]

2. Better understanding of drug effects

Adaptive design trials can sometimes identify a drug effect or ascertain a safety profile more effectively than a comparative fixed design trial, or with a smaller sample size. Their flexibility also allows for investigators to study a broader range of outcomes or more specific questions such as safety within a subset of the study sample.

3. Enhanced patient safety and ethical benefits

Adaptive trials prioritize patient welfare through dynamic protocols that can be tailored according to observed risks and benefits. For instance, adaptations can be made to limit patient exposure to ineffective or potentially harmful treatments identified during the study, ultimately improving participant safety. Alternatively, patients could be switched from the placebo arm to the experimental treatment arm if it becomes clear that the study treatment is highly effective and could significantly benefit subjects in need of treatment.[3]

4. Reduced costs

Adaptive trial designs have the potential to reduce overall study costs by optimizing the use of resources. By optimizing sample sizes based on emerging data and eliminating less effective treatment arms earlier in the trial, adaptive designs can help prevent unnecessary spending on futile endeavors.

Challenges associated with adaptive clinical trial design

The benefits listed above are not guaranteed, and adaptive design is not a universal solution for all trial types. When investigators do decide to implement an adaptive design, the following potential challenges should be kept in mind.

Complex and varied design

Adaptive designs are inherently more complex than their fixed counterparts due to their dynamic nature. The protocol needs to explicitly incorporate all possible scenarios of adaptation, which can lead to varied and multiple designs within a single study. This increased complexity carries increased workload, not only in the trial design but also during its operation and analysis of the results.

Increased resources and expertise required

Conducting an adaptive clinical trial requires significant resources, not only in terms of personnel with adequate knowledge and skills, but also advanced software for real-time data analysis. Thus, adaptive trials tend towards being more expensive than conventional fixed trials, although when very well-designed, they can also save costs by improving the overall efficiency of the trial.

Potential for biased results

Bias can potentially be introduced in an adaptive trial when modifications are made based on interim analyses. For example, treatment effects could be exaggerated or adverse events could be underestimated in an interim analysis, as could occur in the final analysis in a fixed study. However, due to the repeat analyses, there is greater room for potential bias or error to occur in adaptive trials. If an error is made earlier on in the study, it’s possible for the course of the entire study to be changed erroneously, in which case inaccuracies could accumulate and become increasingly detrimental to the quality of trial results (results could even be rendered void/useless).

Complex statistical analysis

Statistical methods used in analyzing adaptive trials are considerably more sophisticated (read: complicated) than those used in fixed-design trials. The most appropriate analytic tools and approaches will vary according to the particular trial’s design, but extra care must be taken to maintain statistical integrity while handling the various adaptations occurring throughout the course of the study. A clinical statistician or data manager with experience in adaptive design clinical trials should be equipped to tackle such projects.

FDA Guidance on adaptive design clinical trials

Recognizing the challenges posed by the innovative yet complex framework of adaptive designs, the Food and Drug Administration (FDA) has issued a formal guidance document which provides recommendations regarding the design and implementation of adaptive designs clinical trials. The FDA’s “Adaptive Designs for Clinical Trials of Drugs and Biologics: Guidance for Industry” can be found by following the link tied to the title of the document.

Best practices for conducting an adaptive clinical trial

As a brief summary, there are some basic best practices for designing and conducting adaptive trials, which we discuss in more detail in this section.

1. Clearly defined objectives

It is critical to have absolute clarity on the objectives and hypotheses of the trial, from its outset. This applies to all clinical trials in general, but in the case of adaptive trials, all amendments should also be defined with precision. Transparency about the intended adaptations and corresponding decision thresholds also need to be clearly delineated.

2. Robust statistical methods

Sponsors/investigators must ensure that the statistical methods employed are sound and robust, giving reliable results that accurately reflect and incorporate the adaptations occurring mid-trial. This typically involves using more complex modeling techniques or simulation-based procedures; in either case, a strong team of statisticians familiar with adaptive trial designs will be beneficial in ensuring scientific validity of the results.

3. Regular reviews and adjustments

Adaptive trials involve regular interim analyses for gaining and incorporating insights from emerging data. These reviews should be carried out by independent committees or statisticians who are appropriately blinded from treatment assignments, hence removing potential bias.

4. Communicate consistently with stakeholders

With changes occurring mid-trial, maintaining clear and open communication with the various stakeholders involved in a trial (i.e., regulators, sponsors, providers, etc.) becomes paramount for maintaining trust and streamlined collaboration throughout the adaptive trial.

5. Consider using adaptive trial simulation to improve design

Running simulations prior to starting an adaptive design clinical trial can help researchers understand how the proposed design might behave under various scenarios and outcomes. These insights can be valuable as they may reveal unexpected problems that could not be elucidated or predicted otherwise due to the complexity and variety of potential outcomes/adjustments that might be made. Results of the simulation can point researchers toward refinements or alterations that can help optimize the final design, mitigating the risk of study failure or biased or unviable results, and safeguarding patient well-being.

Conclusion

In conclusion, adaptive trial design offers a flexible methodology that allows for protocol modifications to be made throughout the course of a clinical research study. The potential benefits of this approach are numerous, including improved efficiency, increased chances of success in terms of answering the research question and meeting trial objectives, enhanced patient safety, and even reduced costs. Nonetheless, their complexity also carries a unique set of challenges, and such studies often require increased planning, complex protocols, and require knowledgeable personnel. As we continue to explore new ways to accelerate drug development and improve outcomes for patients participating in clinical trials, adaptive design clinical trials hold promise for improving efficiency and quality in the field of clinical research.