The US Food and Drug Administration (FDA) wears many regulatory hats, overseeing a range of consumer products and drug treatments. Its Oncologic Drugs Advisory Committee (ODAC) plays a critical role in ensuring the safety of drug products used to treat cancer. ODAC has been at the center of the conversation for many oncologists and researchers, given its recent rulings on clinical trial design and dosage optimization.
In light of these recent decisions, ILCN spoke with John V. Heymach, MD, PhD, Chair of Thoracic/Head and Neck Medical Oncology at MD Anderson Cancer Center. Dr. Heymach, who has led numerous clinical trials investigating targeted and immunotherapy treatments, shared his insights on key ODAC rulings and important lessons for research teams.
ILCN: A recent concern raised during a July 2025 ODAC meeting highlighted the low percentage of US patients enrolled in global trials. What are the biggest logistical challenges in ensuring that global trials include a patient population representative of US demographics?
Dr. Heymach: There are several obstacles to enrolling US patients and ensuring adequate representation in clinical trials. First and foremost is cost. US sites tend to be more expensive to open for a variety of reasons. When companies have a fixed budget for a clinical trial, they need to weigh the number of US patients they can enroll against the total amount of data they can generate globally.
US sites also often face additional regulatory burdens when initiating clinical studies. In many areas, there’s increased competition for US patients because most drug manufacturers seek US approval, where reimbursement rates are often higher. This results in more companies competing for a relatively smaller pool of eligible US patients.
Additionally, more clinical studies are utilizing blinded independent central review (BICR) of imaging, which has increased confidence in the efficacy data from non-US sites and contributed to more reliance on sites outside the US.
Another important reason is the decreasing incidence of lung cancer in the US—about 1%–2% per year recently—likely due to reductions in smoking. In contrast, some regions, such as parts of Asia, haven’t experienced the same degree of decline.
ILCN: The FDA has expressed concerns regarding the safety profiles of certain treatment regimens and emphasized the importance of identifying an optimal dosage.
How can oncologists balance the need for deeper responses, which may be achieved with higher doses, against the benefits of lower doses that might offer similar long-term response rates with fewer toxicities?
Dr. Heymach: Balancing toxicity and efficacy at different doses presents a major challenge. One key issue is that most clinical trials assessing adverse events focus on short-term side effects.
In contrast, long-term efficacy may not become evident for years, meaning we may make dosing decisions based on short-term toxicity data before fully understanding the long-term efficacy profile.
Response rate is a short-term measure of efficacy. For many regimens, you may not see an improved response rate at a given dose; however, you may see longer progression-free survival (PFS) or overall survival (OS) over time.
Another challenge is that requiring randomized studies to compare different doses can significantly delay trials and drug development. For diseases where there is a major unmet need, we must ask: Are we willing to delay access to a potentially beneficial drug in order to more precisely optimize the dose, especially if the drug is already well tolerated?
There’s no single answer; the decision depends on the context. Generally, the greater the unmet need and the fewer the existing treatment options, the more cautious we should be about spending additional time and resources on extensive dose optimization—particularly when the drug has a favorable safety profile.
ILCN: How can researchers design clinical trials to ensure that patients with unmet needs are eligible for studies investigating targeted treatments, while also addressing concerns about overtreatment?
Dr. Heymach: I recommend a flexible approach that balances the value of additional dosage information with the urgency of addressing major unmet needs.
For drugs with a favorable safety profile, it may be reasonable to prioritize making the drug available to patients, with the understanding that post-approval dose optimization studies can still be mandated or conducted later. This avoids a one-size-fits-all requirement for large, randomized dose-finding studies in every setting, which can significantly slow development.
That said, we need data that are robust enough to determine whether a chosen dose is appropriate—particularly when significant toxicities exist, or there is a high risk of overtreatment. However, more flexibility makes sense when the drug is well tolerated and the unmet need is substantial.
ILCN: The FDA has been shifting toward randomized controlled trials to confirm safety and efficacy. Are there situations where alternative approaches should be considered, or where a single-arm design is justifiable?
Dr. Heymach: I don’t believe randomized studies should be required in every case. Randomized trials are often underpowered to truly distinguish differences in efficacy, especially in the early stages. Initial data may suggest similar efficacy between treatment arms, while a separation in outcomes might only become clear with longer follow-up. Relying on early, underpowered comparisons can be misleading.
An alternative approach is to use robust single-arm cohorts within well-defined, comparable populations that can be enrolled sequentially. This can accelerate drug development and provide greater flexibility compared to traditional randomized trials, which are often locked into two or three arms with limited ability to expand or adapt based on emerging data.
Randomized trials may indeed be warranted for drugs with substantial toxicity and an uncertain benefit-to-risk ratio. Single-arm designs remain justifiable when the unmet need is high, the drug appears highly active, and the safety profile is acceptable, making it reasonable to proceed without immediate randomization.
ILCN: What are some important lessons that research teams should keep in mind when designing first-in-human studies or early clinical trials to avoid potential regulatory roadblocks?
Dr. Heymach: One of the most important lessons is to incorporate biomarkers into the initial development plan rather than treating them as an afterthought. If there is a subgroup of patients who derive disproportionate benefit, we want to identify them before launching large, randomized trials, not after.
We’ve seen multiple recent examples—particularly with antibody-drug conjugates (ADCs)—where efficacy in the overall population appears marginal, and only later do we attempt to identify subgroups that benefit more. This is far from ideal.
A second key lesson is to build more robust safety and tolerability datasets earlier in the process, ensuring they are representative of diverse populations. Both steps are critical to facilitating smoother regulatory interactions and avoiding major redesigns or delays later in development.
