Real-Time Oncology Review (RTOR): First Drug Approval

Oncology Clinical Trials

The Food and Drug Administration (FDA) introduced the Real-Time Oncology Review (RTOR) program to expedite the review of new cancer treatments. It allows the FDA to review individual sections of a drug application, instead of the usual requirement that the entire application must be complete before a review can begin. Under RTOR, the FDA can review data from clinical trials as soon as they become available, accelerating the review process and enabling rapid feedback during the clinical trial. As the FDA states, “The Oncology Center of Excellence Real-Time Oncology Review (RTOR) aims to provide a more efficient review process to ensure that safe and effective treatments are available to patients as early as possible, while improving review quality and engaging in early iterative communication with the applicant.”. Since its inception, around a fifth of oncology drug approvals in the US were reviewed under the RTOR program. The benefits of a Real-Time Oncology Review (RTOR) program include a faster review process, improved trial design, and reduced costs, which are explored in more detail below. FDA officials said about 27% of oncology applications are now submitted through the RTOR, while 28% of supplemental applications are submitted through RTOR.^[i]

In 1992, the FDA introduced four distinct and successful approaches known as Priority Review, Breakthrough Therapy, Accelerated Approval, and Fast Track approval of the investigational drug. Under the ‘accelerated approval’ regulation, surrogate endpoints for serious conditions that filled an unmet medical need are reviewed by FDA, allowing faster approval of drugs. A two-tiered system of review times – Standard Review and Priority Review were introduced by FDA under the Prescription Drug User Act (PDUFA). FDA reviews ‘Priority Review’ designated drugs within 6 months (compared to 10 months under standard review).^[ii]FDA Oncology Center of Excellence (OCE) strives to achieve patient-centred regulatory decision-making through innovation and collaboration. To achieve this mission, OCE influences cumulative use of experience of regulatory scientists and reviewers with expertise in drugs, devices, biologics and diagnostics. The Center is responsible for monitoring and expediting medical product development process for oncologic and hematologic malignancies and provides an integrated approach to their clinical evaluation.^[iii]The endpoints in oncology trials are often long-term and drug approval process becomes tedious. Thus, in June 2018, to expedite approval of oncology drugs, OCE launched “Oncology Center of Excellence Real-Time Oncology Review (OCE-RTOR) Pilot Program” for comparatively simpler study designs with straight-forward endpoints.^[iv],[v]

The requirements for a drug to be developed using RTOR are the following:

the drug must be likely to provide substantial improvement over other existing treatments or that they would qualify for the FDA’s Expedited Programs,
the developers must have a straightforward study design,
the clinical trial endpoints must be easily interpreted such as overall survival or response rates.

RTOR program allows the FDA to access and review key data ahead of time, prior to official New Drug Application/Biologics License Application (NDA/BLA) submission. The efficient real-time data review process ensures rapid drug approval without compromising the safety and efficacy of the treatment, by allowing FDA to provide early feedback to the applicant regarding the most effective way to address key regulatory questions.^[vi]This helps to ensure that trials are designed with the necessary endpoints to ensure regulatory approval. The timeline of the RTOR process is summarized in Figure 1.

Figure 1: Real-Time Oncology Review Timeline

Real-Time Oncology Review (RTOR)

Image source: FDA website ^[vii]

As clearly depicted from the RTOR timeline, NDA/BLA approvals can be achieved within 2 to 24 weeks (compared to 6-10 months under priority review). Investigational drugs meeting criteria for other expedited programs (e.g. fast track, priority review) and complex studies are considered for RTOR on a case by case basis.^[viii]Approval of drugs for studies conducted outside of the US, studies including changes with chemistry, manufacturing, and control formulation, studies with pharmacology/toxicology data of supplements, and complex studies (including those with companion diagnostics) are excluded from RTOR program.^[ix]

Examples of drug trials that benefitted from an RTOR program are listed below:

Kisqali® (ribociclib) was the first cancer drug approved by FDA in less than one month under an RTOR program, for the treatment of HR-positive, HER₂-negative breast cancer in post-menopausal women with advanced or metastatic cancer. The real-time review of the study allowed FDA to evaluate and analyse key data in a structured template before formal submission, shortening the approval time to just 3 weeks.^[x]
Adcetris® (brentuximab vedotin) was approved by FDA in mere 2 weeks from the date of application, as the review team was familiar with study details, and already had access to the key data.^[xi]
Kyprolis® (carfilzomib) in combination with dexamethasone for the treatment of relapsed or refractory multiple myeloma is another successful approval within a month under the RTOR program.^[xii]
Other drugs that were approved more rapidly include Keytruda® (pembrolizumab)^[xiii], Tibsovo®(ivosidenib)^[xiv], Kadcyla® (ado-trastuzumab emtansine)^[xv], Venclexta® (venetoclax)^[xvi], and Darzalex® (daratumumab)^{[xvii],[xviii]}.
Piqray® (alpelisib) is the first and only NDA approved for the treatment of patients with a PIK3CA mutation in HR+/HER2- advanced breast cancer, under the OCE-RTOR program. The application was granted priority review by FDA and was successfully processed approximately 3 months ahead of PDUFA approval date.^[xix],[xx]

The Benefits of RTOR

The benefits of RTOR are the faster review process, increased collaboration between FDA and developer, and the improved trial designs that can result from this collaboration. However, drawbacks include the increased workload demands and short turnarounds, as constant updates and assessments will need to be made by both the FDA and the developer. The developer will need to ensure they have the necessary resources and workforce to handle this. Another drawback is the fact that RTOR is relatively new, so how it compares to competitors is not completely understood – it being “difficult to isolate the contribution of RTOR on review timelines since all RTOR applications also participated in other expedited programs”.^[xxi]A research letter published in JAMA Network Open reviewed RTOR trials and concluded “While RTOR is increasingly used to support earlier approvals for oncology indications, these approvals were based on pivotal trials with less robust designs, use of surrogate primary end points, and no requirements to confirm clinical benefit, potentially contributing to clinical uncertainty among patients and clinicians.”.^[xxii] As RTOR is relatively new, there isn’t as much literature on it, but this will increase as more drugs are developed using the program, growing trust in RTOR and establishing its reliability. As such, although RTOR pilot is still a work in progress, it has the potential to ultimately shorten overall review timelines and expedite patient access to effective therapies as both FDA and applicants become accustomed to its procedures.^[xxi]

The Challenges of RTOR

The challenges of RTOR include the management of the Information Requests (IRs) from the FDA along with the ongoing submission planning. These IRs involve short turnaround times, usually between 24 to 48 hours. They may additionally affect future components of RTOR’s rolling submission, as they will need to have incorporate the FDA’s feedback. To manage these intense timelines and constant rapid review cycles, partner with an experienced team capable of coordinating cross-functional communication, who can drive project deliverables around the clock, and manage your submission risks.

Quanticate's team of statisticians and programmers are among the leaders within the therapeutic area of Oncology. With over 30 years combined experience in Oncology studies, we are confident in our ability to discuss your requirements and provide advice about possible ways to increase the chance of a successful study. For more information please submit an RFI.