The Role of Statisticians in Study Design and why to Engage them Early

Pharmaceutical, biopharmaceutical, and biotechnology companies are constantly developing potential therapeutics to test them on human subjects and patients. Much discussion with various key opinion leaders and experts in the therapeutic field has been had as part of the process of planning their clinical development strategy. Key components of this planning include regulatory and corporate objectives, go-no-go decisions, and on a study level, study design, study objectives and endpoints. Well-planned, well-designed, and well-written protocols are essential in accelerating the time it takes to get potential new therapies to patients.

When regulators provide comments and/or review issues on submitted protocols, the clinical and statistical reviewers typically comment on the choice of primary and secondary endpoint, the robustness of the statistical analysis (e.g., alpha control, intercurrent events, and missing data), potential sources of bias, and choice of the control. Involving a statistician at the time of planning, designing, and writing of the protocol will mitigate these review issues, reduce the need for major protocol revisions and ultimately reduce the time to the first patient screened.

Statisticians and the Study Design Team

At the time of planning, it is typical to include medical, regulatory, biostatistics, clinical pharmacology, and clinical operations as primary functions for discussion. It takes a team to achieve success and is best approached when multiple functions with varied perspectives are involved. A statistician is an integral part of the core team that is needed to efficiently design a protocol that meets corporate and regulatory objectives and is successfully moved to execution. A statistician will provide valuable insight into the following important components required for success.

• Determine and define the appropriate endpoints to address study objectives

• Optimization of the study population and endpoint selection/ combination

"The goal of all pharmaceutical, biopharmaceutical, and biotechnology companies is to develop a protocol expeditiously that minimizes study duration and that gains approval by regulatory authorities so therapies can be provided to patients faster"

• Provide guidance toward estimate and framework including considerations of potential intercurrent events and strategies to handle them

• Identify the primary statistical methods to manage missing data

• Identify sensitivity analyses to explore the impact of missing data on the robustness of the study conclusions

• Reduce bias and variability in the collection of endpoints

• Identify circumstances where interim analyses and study adaptations are appropriate and how to align with clinical development needs

• Consideration of potential data to be collected in the current study to plan for future trials

In addition, the statistician is essential in ensuring the sample size properly aligns with the study phase and study objectives. Final decisions about several principal study design features depend on the sample size calculations and need to be carefully considered by the full study team. These include alpha, power, primary and key secondary endpoint selection and definitions, number and type of interim analysis, and study adaptations. The statistician will consider this multitude of factors when assessing sample sizes for various scenarios.

Key Methodology Considerations

When it comes to statistical methodology and choosing the appropriate analysis method for each endpoint, the statistician’s guidance is crucial. Robust analysis plans, appropriate for each study phase, need to be included in the study protocol. Methodology, assessment of statistical assumptions, baseline factors and covariates, and testing of each hypothesis is another way the statistician will contribute to the protocol development.

Furthermore, to demonstrate to the agency that specific data issues have been well thought through and correctly mitigated, the protocol is expected to address the following:

• Identifying intercurrent events and the strategies for handling them

• Planning for missing data and sensitivity analyses to test the robustness of results.

The statistician will discuss these key items with the core development team, agree, and provide detailed descriptions of the analyses/strategies in the protocol.

The goal of all pharmaceutical, biopharmaceutical, and biotechnology companies is to develop a protocol expeditiously that minimizes study duration and that gains approval by regulatory authorities so therapies can be provided to patients faster. To aid in this process, having a statistician as part of the core team during all stages of clinical development is of the essence.