Our shared goal is to reduce the burden of cancer. While treatment has advanced, true victory lies in prevention. In the crucial arena of primary prevention for high-risk individuals and prevention of secondary cancers, our current clinical trial models are failing. We face a logistical and economic impasse that requires a strategic modernization of our approach, guided by new leadership at the U.S. Food and Drug Administration (FDA).
This long-term goal — precision prevention — can end cancer as we know it by preventing suffering and death for those at risk and by helping those not at risk avoid unnecessary tests and treatments.”
The Cancer Prevention Trial Impasse
The gold-standard randomized controlled trial (RCT), the model for therapeutic drug approval, is fundamentally misaligned with the realities of prevention research. Prevention trials are defined by their massive scale and complexity.
For example, the Breast Cancer Prevention Trial (NSABP P-1) enrolled over 13,000 women, and its successor, the STAR trial, enrolled nearly 20,000. The Prostate Cancer Prevention Trial (PCPT) involved over 8,600 men for a period of seven years. These trials are massive and long because the cancer incidence rate in a healthy population is very low. To achieve the statistical power needed for definitive proof of benefit, investigators must enroll huge numbers of participants for many years.
This statistical requirement leads to practical failures. The GOG-0199 ovarian cancer trial required 63 cancer events but accrued only 12, making its objective impossible. Accrual is often slow, especially in targeted populations (e.g., the NRG-CC008 trial for BRCA1 carriers), and long follow-up periods lead to high dropout rates, compromising data integrity.
The economic consequence is a bias against innovation. The high cost and risk of a massive, long-term trial are only justifiable for a large pharmaceutical company with a new, patent-protected molecule. This framework makes it economically unviable to test the preventative potential of vitamins, nutritional supplements, or repurposed generic drugs. The system creates an "infeasibility trap" where promising, low-cost interventions are considered untestable because the evidentiary bar is economically insurmountable.
From "Definitive Proof" to "Reasonable Benefit"
To move forward, we must redefine the evidentiary standard. The current system demands "substantial evidence of effectiveness," the standard for drug approval, which necessitates large-scale randomized controlled trials (RCTs). This creates a paradox: we apply the most stringent evidentiary standards to the lowest-risk interventions (e.g., dietary changes) but accept less rigorous evidence, such as single-arm trials, for the highest-risk scenarios (e.g., treating refractory cancer via Accelerated Approval).
The solution is modeled on the FDA's Accelerated Approval pathway, which allows access to therapies based on endpoints that are "reasonably likely to predict clinical benefit." This shows the agency's capacity for flexibility. We propose applying this principle to cancer prevention. The goal must shift from generating "definitive proof" to demonstrating a "reasonable likelihood of benefit."
This is not about lowering standards, but matching the standard to the context. In prevention, the benefit-risk calculus is different. The potential benefit of even a modest risk reduction is significant, while the intervention's risk, especially for a nutritional supplement, is often very low. Demanding the same certainty as for a cytotoxic chemotherapy agent is not appropriate. A reasonable certainty of a modest benefit is an acceptable trade-off for a very low-risk intervention.
The Methodological Path Forward: Bayesian Statistics and Single-Arm Trials
A "reasonable benefit" standard enables innovative and efficient trial methodologies. First, Bayesian statistical methods are well-suited for this framework. Instead of a simple p-value, Bayesian analysis provides a direct probability of benefit. These methods can incorporate prior evidence to reduce sample sizes and facilitate adaptive trial designs that adjust as data accumulates, making trials faster and more efficient. The FDA's Center for Clinical Trial Innovation (C3TI) is already promoting these approaches.
Second, we must use single-arm trials (SATs). While the FDA has concerns about SATs for oncology treatments, the context of prevention is different. For many prevention questions, the natural history of the disease is well-understood, making comparisons to historical or external control arms reliable. The economic infeasibility of RCTs for non-patentable agents is analogous to rare diseases, where the FDA already accepts SATs. By combining a SAT with safeguards like a well-matched external control arm and a Bayesian analytical framework, we can generate interpretable results efficiently.
A Call to Action for a New Era of Prevention
This modernized approach would create a viable regulatory pathway for testing nutritional hypotheses and repurposing drugs. Sponsors could conduct rigorous yet feasible trials to support specific cancer risk-reduction claims, replacing the weak "qualified health claims" currently used.
With new leadership, the FDA has an opportunity to act. We call on the FDA to:
Issue a Draft Guidance for Industry on clinical trial designs for cancer prevention, formally recognizing "reasonable benefit" as an appropriate evidentiary standard for low-risk interventions and outlining the role of Bayesian methods and single-arm trials.
Convene a Public Workshop with industry, academia, and patient advocates to collaboratively define the parameters of this new framework.
Launch a Pilot Program, similar to the Complex Innovative Designs (CID) program, to help sponsors design and execute the first generation of these innovative prevention trials.
By modernizing its approach to regulatory science, the FDA can remove barriers to progress and enable the development of new, evidence-based tools for cancer prevention.
Enserro, D. M., Gunn, H. J., Elsaid, M. I., Duan, F., & Pugh, S. L. (2025). Challenges to and considerations of designing cancer prevention trials. Journal of the National Cancer Institute Monographs, 2025(68), 49–55. https://doi.org/10.1093/jncimonographs/lgae044