Balancing Simplicity and Complexity in Clinical Trial Design

Designing clinical trials is a nuanced process that often pits the ideal of simplicity against the reality of scientific, operational, and stakeholder demands. While simplicity is a worthwhile goal seeking greater efficiency, reduced burden, and clearer outcomes, it isn’t always the best approach. In practice, oversimplifying a trial without a full understanding of its operational reality can introduce risk, compromise data integrity, and make execution far more difficult than anticipated. 

One of the core challenges in trial design is that you cannot simplify what you cannot see. There's often a disconnect between how a study looks on paper and how it plays out in the real world. For example, an open-label Phase 1 trial with frequent dose-escalation reviews may seem manageable, but in practice, it can require intensive time and attention to review every patient case and involves principal investigators in joint decision-making. These activities, while necessary, contribute to a significant operational burden that isn’t always accounted for in early planning. 

Achieving simplicity requires extensive upfront work. In the pharmaceutical industry, trial design often follows a structured, stepwise path toward regulatory approval. But for the biotech industry, design is frequently shaped by a broader array of stakeholders including regulators, investors, boards, patient advocacy groups, and scientific advisors each with their own set of priorities. This can lead to bloated protocols aiming to satisfy everyone which complicates execution. The pressure to gather more data, ask more questions, and plan for every possible future need often results in avoidable complexity. To counter this, sponsors must be disciplined about identifying which data are essential and which are not, and they must be willing to say no, even when the requests come from influential voices. 

How To Balance Simplicity and Complexity 

Another often-overlooked layer of complexity is patient and site burden. A protocol that appears efficient to the sponsor may be grueling for the sites and patients involved. Decentralized clinical trials, for example, are praised for reducing patient burden, yet they often increase operational demands on study teams. Balancing this dynamic requires meaningful engagement with patient advocacy groups and site advisory councils, not just for feedback on recruitment strategies, but for marking up protocols and flagging operational issues early on. By co-designing studies with the people who will experience them, sponsors can create more realistic and achievable trials. 

It's also important to recognize that complexity isn't always the result of poor planning, it can be a deliberate choice, particularly in the face of uncertainty. In early-phase trials, sponsors often over-collect data to satisfy multiple stakeholders, especially in high-stakes environments where funding and time pressures are acute. Investors may push for comprehensive endpoints to maximize the perceived value of an early-phase program, even if those endpoints don't align with regulatory priorities. Similarly, Contract Manufacturing Organizations (CMOs) and scientific leaders, while guided by regulatory frameworks, may contribute to complexity by layering on additional exploratory objectives. The key is to ensure that any complexity introduced serves a clearly defined purpose and is supported by the obtained data. 

Considerations and Suggestions 

The timing of CMO involvement is also critical. In many companies, particularly smaller biotech firms with limited resources, CMOs are brought in too late to meaningfully influence early-phase design. Ideally, their involvement should begin during the preclinical stage, ensuring that early human studies are grounded in strong scientific rationale. Entering the clinic without a full understanding of the compound’s behavior or exposure risks is not just inefficient, it’s unsafe. 

It’s worth reflecting on whether, as an industry, we’re getting enough out of early-phase studies to design cleaner, more targeted pivotal trials. Overly complex early studies often beget equally complex late-stage trials. While some complexity is inevitable, sponsors should challenge themselves to design Phase 3 studies that are as simple and streamlined as possible. This not only improves the likelihood of regulatory success but also reduces cost, risk, and time to market. 

Balancing simplicity and complexity in clinical trial design is a matter of discipline, visibility, and strategic focus. Sponsors must be clear on their objectives, engage deeply with stakeholders, and prioritize essential data over exhaustive data. Above all, they must remember that simplification is not about removing rigor—it’s about removing unnecessary burdens. At the heart of every great trial is not just good science, but thoughtful, human-centered design. 

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