How to Derisk Clinical Development with Unified Trial Design and Regulatory Strategy

Designing a clinical trial involves significant trade-offs, optimizing for speed and cost while navigating operational complexity and regulatory risk. Despite the opportunities in trial modelling and simulation to improve operational efficiency, accelerate trials, and reduce patient burden, organizations often default to traditional design approaches. This often occurs without considering opportunities to improve upon those clinical trial designs to drive faster, better results.

The perceived reasons for industry reticence include lack of awareness about innovative trial designs and the outcomes that they can achieve, lack of access to the right capabilities and simulation tools, and hesitancy about how favourably regulators may look on these approaches.  

In this Perspectives article, we discuss how statistical simulations, innovative trial designs, and a strong regulatory strategy can help sponsors carve a more effective development path. These insights come from a recent panel discussion hosted by MMS at MassBioHub, featuring Dr. Amanda Beaster, Senior Director of Regulatory Strategy, and Dr. Aiden Flynn, SVP of Strategic Statistical Consulting, who shared their expertise on overcoming challenges and unlocking new opportunities in trial design.

Existing inefficiencies in clinical trials

Despite significant technology advances over the last decade, there has been little meaningful improvement in R&D productivity and overall clinical trial success rates. One major inefficiency, according to Dr. Aiden Flynn, is found in the planning process.  Specifically, statisticians are often brought in too late in the process of designing a trial, usually just to calculate a sample size for a trial already designed by clinical operations.

At this point, key trial decisions are already made and may have been based on flawed assumptions. As Dr. Flynn explained, this siloed approach and late involvement increases the risk of clinical trial failure.

Additionally, some Sponsors let the urgency to get a clinical study protocol finalized and the first patient enrolled sway them from making the necessary resource investment in trial design decisions. Instead, by taking the appropriate time and a cross-functional, collaborative approach to study design, Sponsors can make sure that each study is set up for success with an optimized design and a robust regulatory strategy contributing as much as possible to the overall development program for that drug.

Opportunities for innovative changes

In the context of the described inefficiencies, the rewards of adopting an innovative approach, such as an adaptive clinical trial, or using a synthetic control arm, can be significant. Dr. Beaster highlighted that global regulatory agencies, including the US Food and Drug Administration (FDA), are more receptive to innovative clinical trials in rare diseases. For instance, FDA has allowed use of natural history data to replace the need for patients being enrolled in a placebo arm. However, there is no fixed definition of a complex or innovative trial design because what is considered innovative, or novel can change over time.

As these clinical trials become more mainstream, the regulatory risk of implementing them decreases and Sponsors should consider these clinical trial designs in order to ensure that they are considering all possibilities. More than a cost benefit, innovative trial designs are sometimes needed to make a trial feasible and ethical.

More broadly, innovative designs enabled by simulation can help to reduce the sample size and increase the overall probability of success. Dr. Flynn shared an example of an RSV clinical trial that originally planned to alternate between northern and southern hemispheres to collect enough patient data. However, this approach would have significantly extended the timeline. A key challenge was how to collect viral load data efficiently while minimizing patient burden. The study considered two methods:

1. A highly invasive approach involving a tube inserted into the lungs, which provided high-quality data but was difficult for infants and distressing for parents.
2. A non-invasive nasal strip that allowed for frequent data collection but raised questions about data accuracy.

By using statistical simulations, the team demonstrated that the nasal strip method was the most statistically powerful approach due to the ability to take repeated measures. This simulation-driven design allowed the Sponsor to complete the trial in a single winter season in the northern hemisphere, reducing costs and accelerating timelines while maintaining scientific integrity and prioritizing the patient experience.

Nevertheless, as Dr. Flynn pointed out, an innovative approach is not the answer for every situation as there may be times when a traditional design is the best approach. By conducting proper due diligence through simulations and strategic statistical input, Chief Medical Officers (CMOs) and clinical development leaders can initiate the clinical trial with the reassurance that their selected approach is the best one and communicate that reassurance to their investors and external stakeholders.

How to reducing the risk in Phase 2 clinical trials

Phase 2 clinical trials carry some of the highest risks in drug development, with an average success rate of 28 percent (Citeline). However, according to Dr. Flynn, by applying better clinical trial design principles and using statistical simulations, Sponsors can substantially increase their success rates to approximately 67 percent.

Simulations have the benefit of not only optimizing clinical trial design but weeding out potential missteps before they even happen. Indeed, retrospective analysis of past clinical trials shows that studies that did not incorporate simulation and strategic design underperformed or failed entirely.

By integrating simulation-driven insights early in Phase 2, companies can reduce uncertainty, improve decision-making, and significantly enhance their chances of progressing to Phase 3 with a viable, well-supported clinical study design.

Overcoming regulatory barriers

Aligning regulatory experience with statistical and data strategy can help Sponsors navigate through these complexities of implementing novel designs, which can be a barrier for many. For instance, at MMS, our clinical data strategists bring deep experience of implementing complex clinical trial designs and routinely help Sponsors understand how to operationalize effectively. From a regulatory standpoint, Sponsors benefit from guidance as to whether global health authorities will be receptive to the complexities of the design and whether the chosen approach could support registration.

Dr. Beaster emphasized the importance of liaising with regulators as early as possible when considering an innovative design, as well as interacting with CROs and sites. But how early is early?  She advised, saying “Early, meaning as soon as you have agreement internally.” Regulatory strategists, working alongside statistical consultants, play an instrumental role in demonstrating to agencies how proposed clinical trial designs align with established methods, making it easier for regulators to assess and approve innovative approaches.

Derisking clinical development

With pressure to do more with less, overall trial complexity, and economic headwinds, biotech companies are constantly weighing their options to either stick with traditional clinical trial designs or take a more strategic path incorporating statistical innovation and early regulatory engagement. The discussion at MassbioHub made one thing clear, a lack of cross-functional collaboration in clinical trial design decisions can be a mistake that increases overall risk, despite non-adaptive options feeling familiar.

Effective development programs involve collaboration between experienced statistics, regulatory, and clinical teams. Through thorough discussions, these teams can work together to find the position that has the highest likelihood of success. By leveraging simulation and strategic trial design capabilities, breaking down functional silos, and engaging regulators early, Sponsors can set their trials up for success. In the end, this decision can lead to reduced costs, improved patient experience, and the delivery of better treatments faster.

For a deeper dive into these topics, watch our webinar here: Advancing Clinical Development with Innovative Trial Design and Regulatory Strategies