The FDA review process for oncology therapeutics is necessarily rigorous, but during that process cancer patients may be waiting to access new therapies—a matter of life or death in some cases. The FDA has been attempting to accelerate time to approval for oncology therapeutics for the past several years with accelerated approval, priority review, breakthrough designation and other programs and designations (table 1). Recently, the FDA’s Oncology Center of Excellence launched a pilot program for oncology therapeutics called Real-Time Oncology Review (RTOR). Under this program, manufacturers can submit analyses of their clinical data to the FDA as they become available but before a formal supplemental new drug application or supplemental biologics license application is submitted. After submission, the drug can potentially be approved in a matter of weeks or even days.

Currently, the RTOR pilot is only accepting applications for supplemental indications for drugs that have already been approved by the FDA, meaning that new molecular entities (NMEs) are ineligible. Once approved for the program, sponsors work closely with the FDA as they process and analyze clinical trial data to ensure that their data will be acceptable once they’re ready to submit the official application. This collaboration is facilitated by the assessment aid, a shared document between the manufacturer and the FDA to streamline the process of providing feedback on the manufacturer’s position. Through tight collaboration, the entire process—from announcing top-line data to the FDA granting approval—can take as little as 20 weeks, according to the FDA.

So far, there have been four oncology therapeutics (Kisqali, Keytruda, Kyprolis, Adcetris) that have been granted new or extended indications via RTOR, and another four (Tibsovo, Kadcyla, Venclexta, Darzalex) that are currently being reviewed under the RTOR program.

At first, this may sound like a dream come true for manufacturers eager to get their therapies to patients as quickly as possible, but to gain access to this program, we have seen that several criteria must be met:

1. Unmet need: In order to be eligible for RTOR, the proposed indication must address a high unmet need. The approval of Adcetris in peripheral T-cell lymphoma (PTCL) is a good example of this criterion: Adcetris became the first FDA-approved therapy in this rare and fast-growing form of non-Hodgkin lymphoma. Kisqali is another example: It became the first CDK4/6 inhibitor to be approved for pre- and peri-menopausal women with HR+, HER2- metastatic breast cancer. Venclexta, which was recently accepted for review, also addresses an unmet need by providing a fixed-duration, chemotherapy-free treatment option for frontline chronic lymphocytic leukemia (CLL) patients.
2. Sufficient body of evidence: In addition to addressing a significant unmet need, the clinical trial itself must be straightforward, with its results clearly demonstrating a significant benefit. For example, Keytruda’s label expansion in non-small-cell lung cancer (NSCLC) was based on the KEYNOTE-189 trial, in which Keytruda showed a hazard ratio of 0.49 for median overall survival—or, in other words, a 51% reduction in risk of death. Similarly, the Darzalex plus Rd combination currently undergoing review showed a 45% reduction in risk of disease progression or death compared to Rd alone in the MAIA trial. Furthermore, while the RTOR program does not explicitly accept applications based on real-world evidence (RWE), a robust body of RWE from approved indications appears to improve the chances of approval through the RTOR program.
3. Close collaboration with the FDA: Once a sponsor contacts the FDA with a promising candidate for RTOR, they will need all hands on deck to supply the FDA with the data they request for the review. Seattle Genetics CEO Clay Siegall recounted how the FDA often requested certain analyses of the Adcetris trial data within 24 hours, which was achieved by his team working late nights and over the weekends. The payoff? Seattle Genetics wrote up the application in five weeks compared to an expected three months and, once submitted, the FDA approved Adcetris’s application in 11 days.

The promise of the RTOR program means that gaining access is going to become more and more competitive. Manufacturers will need to prioritize clinical programs with RTOR in mind and think about three key questions:

• How would RTOR allow a clinical program to support a specific group or subgroup of patients more quickly?
• Where would clinicians and thought leaders advocate for RTOR to be applied to a compelling new molecular entity (NME)?
• If a clinical program is approved under RTOR, what additional evidence will need to be generated to support strong commercial adoption?

What does the future hold for this pilot program? Currently, the RTOR program is only accepting new indications for existing products. However, a recent white paper written in collaboration by stakeholders from the FDA, manufacturers and patient advocacy groups suggests that ultimately the RTOR program could expand to new molecular entities.