The Blind Spots in Early Oncology Development: The Risks We Don’t See Are Often the Ones That Matter Most

One of the reasons I enjoy working in early oncology drug development is that no two studies are ever exactly alike. Every investigational therapy raises new questions, every protocol challenges assumptions, every patient teaches us something we didn’t know before. That’s what makes early development so intellectually rewarding. However, it’s also what makes it so challenging.

When people think about risk in Phase 1 oncology, they usually think about the obvious things: dose-limiting toxicities (DLTs), serious adverse events (SAEs), and unexpected safety signals. These risks are closely monitored, discussed regularly, and everyone on the study is watching for them.

But after nearly two decades in oncology drug development, I’ve come to realize that some of the greatest threats to an early development program aren’t the risks everyone is looking for. Instead, they’re the blind spots no one realizes exist until much later, making them much harder to correct.

Blind Spot #1: Believing the Protocol Answers Every Question

Every Phase 1 protocol is written with extraordinary care. Hundreds of hours go into every eligibility criterion, dose-escalation rule, safety assessment, and schedule of events. Yet one thing I’ve learned is this: the protocol is never the study itself, but rather the starting point. The moment the first patient is enrolled, the protocol begins interacting with reality. Investigators encounter situations that weren’t anticipated, patients present with clinical nuances that don’t fit neatly into predefined criteria, and questions emerge that seemed obvious during protocol development but become surprisingly complicated in practice. The blind spot lies in assuming that because something is written clearly, it will automatically be interpreted consistently. And trust me it won’t. That’s why medical judgment remains just as important as protocol design.

Blind Spot #2: Focusing on Individual Events Instead of Emerging Patterns

Early in development, it’s easy to view every adverse event as an isolated occurrence. For instance, one patient may develop a laboratory abnormality, another may experience fatigue, and someone else may require a dose interruption. Individually, these events may not seem particularly concerning but medicine doesn’t speak in isolated events; it speaks through patterns. Some of the most important safety observations I’ve encountered didn’t become meaningful until several seemingly unrelated pieces began to fit together. This is one of the reasons medical monitoring extends far beyond reviewing individual cases. The real value often comes from connecting observations that initially appear unrelated.

Blind Spot #3: Underestimating Operational Variability

One of the biggest surprises for people new to early oncology development is how much impact operational execution has on scientific outcomes. We like to believe that every site interprets protocols the same way, that every eligibility review follows identical reasoning, and that every investigator approaches novel toxicities in a similar manner. However, reality is far more complex than that. Even highly experienced investigators bring different perspectives to the table, and this is not a criticism; it’s simply human nature. Without proactive communication, these differences gradually introduce variability into a study, making it more challenging to address. Recognizing these differences early on becomes crucial for effectively managing and mitigating their impact. 

Blind Spot #4: Mistaking Speed for Progress

Every biotech company wants momentum, driven by enrollment updates, dose-escalation milestones, expansion cohorts, and positive announcements. These achievements hold significance, but I’ve come to realize the importance of asking a different question: “What have we actually learned?” Moving quickly through cohorts doesn’t necessarily mean we’re generating meaningful knowledge. Sometimes, the most valuable decision isn’t escalating to the next dose but rather taking enough time to fully understand the one we’ve already explored. Progress in Phase 1 isn’t measured only by how quickly the study moves. It’s measured by how much confidence each decision creates for the next one.

Blind Spot #5: Waiting Too Long to Ask Difficult Questions

One pattern I’ve noticed throughout my career is that uncomfortable questions rarely become easier with time. If eligibility criteria are creating confusion during the first few patients, they probably won’t become clearer on their own. Similarly, if investigators are interpreting the protocol differently, that variability is unlikely to correct itself. Even if a recurring safety observation feels unusual, waiting another month rarely makes it less important. One of the most valuable habits I’ve developed is asking difficult questions earlier than feels comfortable. This isn’t because every concern becomes a problem, but because every meaningful problem begins as a question.

Blind Spot #6: Assuming Manufacturing Ends Once the Product Is Released

Cell and gene therapies have changed the way we think about early development. Manufacturing is no longer simply an operational milestone before treatment; it’s now an integral part of the clinical strategy. This includes vein-to-vein timelines, product consistency, chain of custody, release testing, scheduling, and more. Each of these factors can influence the patient’s experience and the interpretation of study results. Scientific innovation and manufacturing execution are becoming increasingly intertwined, a blind spot that many organizations don’t fully appreciate until programs become more complex.

Blind Spot #7: Forgetting That Investigators Are Learning Too

Sponsors often spend months immersed in the protocol before a study opens. In contrast, investigators don’t have that luxury. They’re balancing clinical care, multiple research programs, institutional requirements, and patient responsibilities simultaneously. Even the most experienced investigator is learning the therapy alongside the sponsor. This dynamic requires a shift in how we should think about communication. Medical monitoring isn’t simply answering questions. It’s helping investigators gain confidence while the entire program is still evolving. The quality of those early interactions often shapes the overall quality of the study itself.

Blind Spot #8: Treating Medical Monitoring as a Safety Function Instead of a Development Function

This may be the blind spot I encounter most often. Medical monitoring is still sometimes viewed primarily as a mechanism for reviewing adverse events. In reality, experienced medical monitors contribute far earlier and much more broadly. We’re reviewing eligibility before enrollment, identifying protocol ambiguity, recognizing operational trends, supporting dose-escalation discussions, helping investigators navigate uncertainty, and connecting seemingly unrelated observations across sites. In many ways, medical monitoring becomes an integral part of the scientific development strategy itself, and when organizations recognize that early, studies tend to benefit.

The Biggest Blind Spot of All

If I had to choose one blind spot above all the others, it would be this: believing that the greatest risks are the ones everyone can already see. In my experience, that’s rarely true. The obvious risks receive attention, are discussed during governance meetings, are tracked carefully, and are escalated appropriately. The greater danger often comes from subtle issues that quietly accumulate beneath the surface. These may include recurring investigator questions, inconsistent eligibility interpretations, minor operational delays, or patterns that haven’t yet become apparent. It is during these moments that experience truly matters. Not because experienced teams can predict the future, but because they have learned to look for potential risks before others do.

A Final Thought

Early oncology development has always been about exploring the unknown, which makes it both exciting and challenging. Every promising therapy begins its clinical journey surrounded by uncertainty. Our responsibility isn’t to eliminate that uncertainty, as it’s an impossible task. Instead, our responsibility is to recognize it early, ask better questions, remain intellectually curious, and make thoughtful decisions as new evidence emerges.

The most successful Phase 1 programs aren’t successful because they avoid every challenge. They’re successful because they identify blind spots before those blind spots become barriers. After nearly two decades in oncology drug development, I’ve come to believe that some of the most important work we do isn’t solving the problems everyone already recognizes. It’s about spotting the ones no one else has noticed yet. 

In early oncology development, the future of a program is often determined not by the risks we prepare for, but by the ones we have the experience to recognize before they fully appear.