Implementing Adaptive Designs: Operational Considerations, Putting It All Together

Abstract

The use of adaptive clinical trial designs for a drug development program has clear advantages over traditional methods, given the ability to identify optimal clinical benefits and make informed decisions regarding safety and efficacy earlier in the clinical trial process. However, operational execution can be challenging due to the added complexities of implementing adaptive designs. These complexities deserve additional attention. Key operational challenges occur in several areas: availability of statistical simulation tools for clinical trial modeling at the planning stage; the use of trial simulation modeling approaches to ensure that the trial is meeting expected outcomes; and challenges regarding rapid data collection, clinical monitoring, resourcing, minimization of data leakage, IVRS, drug supply management, and systems integration. The purpose of this chapter is to highlight several operational challenges that must be taken into consideration in conducting an adaptive clinical trial. Adaptive design implementation strategies are also discussed in this chapter.

Appendix: Process Flow Example

We previously discussed that business process modeling is an activity that allows for the representation and documentation of key clinical trial activities, so that proposed operational processes may be analyzed and optimized. In this capacity, business process modeling is a useful tool that allows for the optimization of an adaptive clinical trial design. Described below are the essential elements of the trial design planning process, using business process modeling, which can occur in four general stages.

Stage 1: Compound and portfolio evaluation. In this stage, the drug manufacturer will proceed with a portfolio management process to make an assessment of which compound will be developed, based on the scientific, technical, medical, and commercial information required to assess the probability of technical success of the molecule. A decision will be made at the end of this evaluation period to either proceed or not proceed with the development of the compound. The information gathered in the stage will be utilized as a part of the adaptive clinical trial development approach.

Stage 2: Trial design simulation. In this stage, commercial software or custom software applications will be utilized to simulate key features of the proposed adaptive design and assess operating characteristics of the design. Data from other trials with this compound might be used to understand the uncertainty of treatment effect assumptions. The relative impact of the adaptive design trial on overall development should be considered. Examples of specific adaptive design requirements may include dropping or adding treatment arms; terminating the trial during an interim analysis due to efficacy, futility, or safety; changing patient randomization scheme; re-estimating the sample size; selecting subpopulations; and any combinations of the above.

Stage 3: Operational simulation. In this stage, the desired adaptive design is simulated to ensure that the design can actually be executed at the operational level. Simulations will include regulatory submission and approval timelines based on proposed country selections and study protocol, patient recruitment model, data submission timelines (all data elements required for data collection and statistical analysis), pre-planned interim analysis and DMC milestones, drug supply, compliance model, data cleaning activities, resource allocations, and final proposed program timelines. It is important to note that operational simulation efforts may indicate that the proposed study design may not be operationally feasible, which will require modification of the final study design to ensure successful implementation. The process of simulation is a critical element and should not be underestimated.

Stage 4: Operational execution plan. In this stage, given finalization of the intended design and appropriate operational simulation to ensure that the trial can be successfully executed, a comprehensive operational plan must be developed to ensure that the appropriate systems are in place and can be fully integrated to meet the final project plan deliverables. Business process flow diagrams are essential to ensure that each operational function understands how the trial will be executed, how the data will flow through the trial, and what key decisions need to be made at specific time points within the trial. This is an essential step in the process when working with multiple business partners, and multiple external vendors. As discussed previously, the planning and design process may take several months to complete, but is well worth the effort (Fig. 11.1).

Fig. 11.1

An adaptive design process flow: response-adaptive allocation design