Regulatory guidance plays a critical role in clinical trial development, but it cannot anticipate every question that may emerge during the development of a program. When guidance is absent, outdated or inconsistent across authorities, sponsors have legitimate room to exercise judgment. However, that flexibility should be approached as conditional rather than permissive. Flexibility in a program’s design does not change the level of scrutiny that regulators will apply to the evidence sponsors provide.
This distinction requires sponsors to look beyond whether a program simply satisfies written guidance and consider the regulatory decision the evidence will ultimately need to support. While a study can follow available recommendations to the letter, it may fall short on generating the essential evidence needed to resolve the questions regulators will pose during review. By considering the eventual regulatory decision throughout development, sponsors can ensure that the evidence collected can support a clear conclusion about a therapy.
A compliant trial is not necessarily a decision-ready trial
Bringing a novel drug or therapy to market can take up to 12 years, on average. At the same time, pressure to accelerate this process continues to grow. According to Deloitte’s 2026 Life Sciences Outlook, 41% of surveyed biopharma executives responded that R&D productivity or product-development efficiency are a priority for managing costs in 2026. This long process means that clinical trial design decisions are often made years before regulators evaluate the complete evidence package.
Sponsors must therefore consider the eventual regulatory decision from the outset and think ahead, defining what the study ultimately needs to demonstrate for the intended treatment population. This requires sponsors to consider how different study outcomes could affect the strength and interpretability of the evidence, rather than focusing only on whether the trial is scientifically sound or follows available guidance.
For example, an overly optimistic assumption about effect size can leave a study underpowered and unable to clearly identify a true treatment effect. Similarly, a heterogeneous patient population can dilute the observable treatment effect. In both cases, the evidence generated may be statistically valid but insufficient to support a clear conclusion about clinical benefits.
Small development choices can become large evidence problems
Regulatory risk rarely comes from just one decision. Instead, it emerges through a series of individual design choices made throughout the development stage. Decisions regarding dose selection, the relationship between endpoints or biomarkers and patient-relevant outcomes, and study duration can all create unique challenges that make efficacy and safety findings harder to interpret.
Sponsors should be wary of flexibility when approaching regulatory standards to avoid creating downstream consequences. Within every clinical trial, sponsors are statistically planning and accounting for how real-world complications can impact the evidence. Decisions that appear reasonable at one point may become costly and difficult to address once a trial is underway. To avoid these disruptions, sponsors must consider not only whether a design choice is permitted, but how it could impact result interpretation.
Another source of potential uncertainty is statistical planning. Sponsors should define estimands, including handling of intercurrent events, and use sensitivity analyses to test assumptions around missing data and alternative interpretations. This methodical approach can preserve the interpretability of the collected evidence when results do not unfold as expected.
Regulatory intelligence should shape decisions before submission
Direct engagement with regulators at multiple points during development can help sponsors pinpoint uncertainty, but engagement alone does not reduce regulatory risk. Sponsors must translate concerns raised by regulators into actionable commitments within the development of a trial. Depending on the feedback provided, that could mean everything from reevaluating dose justifications to updating an endpoint or biomarker strategy or changing the evidence plan.
Regulatory intelligence also extends outside of interactions between sponsors and regulators. Publicly available information, such as Complete Response Letters, can show how regulators have evaluated uncertainty in other products, indications and evidence packages. Sponsors can compare those precedents against their own pharmacokinetics/pharmacodynamics strategy, dose justification, endpoint or biomarker selection, and evidence planned for the intended population. Identifying these patterns will not determine the outcome of a new submission. However, it may assist in recognizing questions that warrant attention earlier.
Build for the decision that comes later
Regulatory guidance is never static. This means that flexibility will always exist within the development of new therapies. The risk arises when that uncertainty goes unexamined until regulators are reviewing an evidence package that can no longer be readily changed. Sponsors can manage this risk by continually assessing whether the evidence they generate will support a clear regulatory conclusion about efficacy, safety and benefit-risk.
When written guidance does not provide a complete roadmap, designing around the eventual regulatory decision can provide a more durable standard for development. This keeps sponsors from trying to anticipate every question that regulators could ask and allows them to focus on generating evidence capable of supporting the decision regulators ultimately need to make.
About Zainab Funsho PhD, Head, Regulatory Affairs, IQVIA
Dr. Zainab Funsho is a regulatory affairs and drug development leader with 17 years of combined pharmaceutical industry and CRO experience in drugs and biologics development. She provides strategic guidance for U.S. and global development pathways, including INDs, CTAs, NDAs, BLAs, and marketing authorization applications. Funsho has extensive expertise in CMC strategy, regulatory agency meetings, technical and regulatory documentation, and Orphan and Priority designations. Her therapeutic experience spans oncology, hematology, neurology and dermatology.
