Why Early Oncology Drug Development Requires a Different Mindset

A common misconception I encounter is that early-phase oncology studies are simply smaller scaled-down versions of late-phase trials. However, they differ significantly. While they share similarities like protocols, investigational sites, eligibility criteria, safety reporting, endpoints, and patients receiving investigational therapy, the environment in early oncology development is entirely different. The questions are different, the risks are different, the decisions are different, and perhaps most importantly, the mindset has to be different.

Throughout my career in early oncology drug development one thing has become increasingly clear to me: Success in Phase 1 isn’t determined by how well you follow a process. Instead, it’s determined by your ability to think critically and creatively. In early development, you’re rarely working with certainty. Instead, you’re helping create it.

You’re Not Confirming What You Know

One of the biggest differences between early- and late-phase development lie in the primary objective of the study. By the time a therapy reaches Phase 3, we usually have a reasonable understanding of its biological mechanisms. We’ve seen signals of activity, gained insights into its safety profile, and begun defining the patient population.

In contrast, late-phase development primarily focuses on confirming existing findings. Early development, on the other hand, is something else entirely. It’s exploration. Every patient contributes to our understanding of the therapy, every safety event teaches us something, every pharmacokinetic result, every biomarker, every dose level, and every clinical observation helps shape the future trajectory of the program.

This entails a very different responsibility. Instead of validating existing knowledge, you are actively building upon it.

There Are Far More Questions Than Answers

One thing I appreciate about Phase 1 is its honesty. Nobody pretends we have everything figured out. We’re asking fundamental questions, such as whether the dose is appropriate, what toxicities emerged, how to manage these toxicities, whether the mechanism behaves as expected, whether biomarkers support the biology, which patients appear to benefit, and whether development should continue.

There are no shortcuts to these answers. These answers emerge one patient at a time, requiring patience, humility, and thoughtful clinical judgment.

Medical Judgment Carries More Weight

In later-phase studies, established patterns often guide decision-making. However, in Phase 1, many situations have no precedent. 

For instance, a patient may develop unexpected toxicity, an investigator may pose a question not fully addressed by the protocol, laboratory abnormalities may evolve differently than anticipated, or an emerging safety trend may not be clearly understood. These situations require more than protocol knowledge; they require judgment.

I’ve always believed that this is where medical monitoring creates some of its greatest value. It’s not because we know all the answers. It’s because we’re comfortable making thoughtful decisions while the answers are still unfolding.

Protocols Can’t Anticipate Everything

Early-phase oncology protocols are incredibly detailed, but no matter how carefully they’re written, they cannot predict every clinical situation investigators will encounter.

This is simply the nature of first-in-human and early-development research. Patients don’t always behave the way preclinical models predicted, novel mechanisms introduce novel questions, and unexpected observations emerge.

These observations don't indicate that something went wrong; they signify that we’re learning. The strongest teams recognize that flexibility and scientific discipline exist simultaneously. Protocols provide structure, while clinical judgment provides adaptability, and both are essential.

Dose Escalation Is About More Than Finding a Number

When people think about Phase 1 oncology, they often think about dose escalation, including finding the maximum tolerated dose (MTD), identifying dose-limiting toxicities (DLTs), and determining the recommended Phase 2 dose (RP2D).

These milestones are undoubtedly important, but over the years, I’ve come to think of dose escalation differently. It’s really about understanding the biology of the therapy. How does the therapy behave? What happens as exposure increases? When does efficacy begin to emerge? How do safety and activity interact? The dose isn’t simply a number, but a reflection of everything we’re learning about the therapy.

That’s why dose-escalation discussions are often among the most intellectually rewarding conversations in oncology development.

Speed Matters But Learning Matters More

Every biotech company wants to move quickly and I understand why. Patients are eagerly awaiting treatment, investors are closely monitoring the company’s progress, resources are limited, and competition is fierce. But one thing early development has taught me is that speed without learning leads to short-term success rather than long-term sustainability.

While enrolling patients quickly is important, understanding what those patients are teaching you is even more important. Sometimes, the most valuable decision isn’t about opening another cohort of patients but to pause and thoroughly understand the ones you’ve already treated. Early development rewards thoughtful progress over rapid progress.

The Medical Monitor Is Part of the Scientific Team

One aspect of early development that I particularly enjoy is how closely medical monitoring becomes integrated with scientific decision-making.

We’re not simply reviewing safety reports. We’re participating in the evolution of the program. We’re reviewing eligibility, interpreting emerging toxicities, supporting dose-escalation decisions, identifying operational challenges, and helping investigators navigate novel situations. We’re even recognizing patterns that may influence future cohorts.

Medical monitoring becomes an integral part of the scientific conversation, which is one of the reasons I find early oncology development so rewarding. Every discussion has the potential to shape the future of the therapy.

Every Decision Echoes Into Later Development

Something I often remind other physicians is that many of the decisions made during Phase 1 don’t stay in Phase 1. The eligibility criteria you refine today may become tomorrow’s registration study. The toxicity management strategy you develop now may eventually become routine clinical practice. The biomarkers you explore in early development may later define patient selection. 

Even seemingly small operational decisions often influence years of subsequent research. This is an incredible responsibility and it also explains why thoughtful decision-making matters so much during the earliest stages of development.

Curiosity Is More Valuable Than Certainty

If there’s one quality I think that truly defines exceptional early-phase physicians, it isn’t confidence, but curiosity. It’s the willingness to ask another question, to challenge assumptions, to explore unexpected findings rather than dismiss them, and to remain open when the biology surprises us.

Oncology has taught me repeatedly that certainty can become a liability. Curiosity, on the other hand, keeps science moving forward, and early development depends on people willing to stay curious even when the answers aren’t immediately obvious.

A Final Thought

People often describe Phase 1 as the beginning of clinical development. While technically, that’s true, I believe it signifies something more profound. It’s where possibility first meets reality. It’s the point where years of laboratory research begin interacting with real patients. It’s where assumptions become evidence, where ideas become data, and where uncertainty slowly becomes understanding.

This transition requires a different mindset than any other stage of drug development. It requires leaders who are comfortable asking difficult questions, medical monitors who recognize patterns before they’re obvious, investigators who embrace uncertainty without compromising patient safety, and sponsors who understand that learning is just as valuable as speed.

The future of every oncology program is shaped by what happens during those earliest studies. After nearly two decades in this field, I’ve come to believe that building great Phase 1 programs isn’t simply about developing better therapies. It’s about developing a better way of thinking.