The FDA Oncology Center of Excellence commenced the Real-Time Oncology Review (RTOR) pilot project in February 2018 to facilitate earlier submission of topline results and datasets to support an earlier start to the FDA application review. RTOR was initially begun to support supplemental drug applications to add new indications, dosing regimens, or other clinical information to the prescribing information, but was later expanded to include original new drug applications and biological license applications for new molecular entities (NME). From February 2018 to April 2020, RTOR was used to support the submission and review of drug approvals for 20 oncology applications (11 for solid tumor and nine for hematologic malignancy indications). Two were NME drug approvals and 18 were supplemental approvals. All of the applications received priority review and nine (45%) applications had received breakthrough therapy designation status. FDA received the RTOR submissions a median of 5.7 weeks (range 1.7–16.2 weeks) prior to the full application submission. The median time from application submission to FDA approval was 3.3 months (range 0.4–5.9 months). RTOR was also integrated with other review programs including the Assessment Aid and Project Orbis programs. Innovative regulatory processes are critical to expedite the rigorous review of impactful products across the FDA.

The FDA Oncology Center of Excellence (OCE), established in January 2017, has launched multiple initiatives consistent with its mission of achieving patient-centered regulatory decision-making through innovation and collaboration (1). One of these initiatives is the Real-Time Oncology Review (RTOR), launched in February 2018 (2).

In a typical FDA drug review process, efficacy and safety data are submitted with all other elements of a drug application submission (administrative information, summary documents, clinical study reports, manufacturing information, and nonclinical study reports). However, the process of assembling a drug application for submission takes several months due to the volume and details required. The OCE developed RTOR to facilitate earlier submission of critical efficacy and safety data for FDA's evaluation. RTOR is different than the existing Rolling Review mechanism, in which complete modules can be submitted prior to a complete application.

In general, submissions considered for RTOR should meet certain criteria, such as drugs likely to demonstrate substantial improvements over available therapy, which may include drugs granted breakthrough therapy designation (BTD) or those that qualify for priority review (3, 4). BTD and priority review are established Expedited Programs within FDA. Currently, RTOR remains as a pilot program in contrast to the established FDA Expedited Programs, which are set forth from laws and regulations (5). To be selected for RTOR, the study designs should be straightforward and the clinical trial endpoints should be easily interpreted (e.g., overall survival, progression-free survival, or durable response rates).

RTOR involves early iterative engagement with the submitting drug company (called the applicant) to negotiate the submission timelines for RTOR components and the full application submission. To initiate an RTOR submission, FDA requires the topline efficacy and safety results from the pivotal clinical trial(s). At this stage, the applicant should have already completed the database lock for the clinical trial. RTOR is not designed to receive live updates of clinical trial data.

This article summarizes the initial experience (February 2018 to April 2020) with the RTOR program, which was used to support drug approvals for 20 oncology applications at FDA Center for Drug Evaluation and Research (CDER). This RTOR workload represented 25% of the priority review oncology approval workload (N = 80) during the same period. Initially, RTOR was evaluated for supplemental drug applications, which add new indications, dosing regimens, or other clinical information to previously approved drugs. In December 2018, RTOR was expanded to include original drug applications, also known as new molecular entity (NME) applications.

From February 1, 2018, to April 30, 2020, FDA granted 20 approvals for applications that used the RTOR program (Fig. 1). The approvals include 18 supplemental drug applications, which provide for new indications, dosing regimens, and/or other clinical information in the prescribing information. With successful implementation of RTOR, NMEs were accepted into the program. To date, there have been two NME approvals conducted under RTOR (6, 7). Both small molecule and biologics (e.g., mAbs, antibody–drug conjugates, etc.) applications were included in RTOR. The application breakdown consisted of two original new drug application (NDA), 11 supplemental NDA, and seven supplemental biological license application (BLA) approvals. Applications for cellular and gene therapies and vaccines, which are submitted to the Center for Biologics Evaluation and Research (CBER), are not included with the current implementation of RTOR.

Figure 1.

FDA approvals using RTOR (February 2018 to April 2020). CSR, clinical study report. Asterisk indicates full drug name: brentuximab vedotin; ado-trastuzumab emtansine; and lenvatinib mesylate.

Figure 1.

FDA approvals using RTOR (February 2018 to April 2020). CSR, clinical study report. Asterisk indicates full drug name: brentuximab vedotin; ado-trastuzumab emtansine; and lenvatinib mesylate.

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The scope of the RTOR applications was approximately evenly split between solid tumor [11 (55%)] and hematologic malignancy [9 (45%)] indications. The most common indications were for breast cancer [5 (25%)], chronic lymphocytic leukemia [4 (20%)], and gynecologic malignancies [3 (15%)], and two applications each (10%) for acute myeloid leukemia, multiple myeloma, and gastrointestinal malignancies.

All of the RTOR applications [20 (100%)] qualified for priority review, which translates to a 6-month review timeline for supplemental drug applications and 8-month review timeline for NME marketing applications under the current Prescription Drug User Fee Act (PDUFA). Almost half [9 (45%)] of the RTOR applications had BTD granted for the proposed indication.

The majority of the RTOR applications were based on randomized clinical trials. Fifteen (75%) relied on a single-randomized trial. One application relied on two randomized trials. The remainder [4 (20%)] relied on single-arm trials. Clinical trial population size ranged from 28 to 121 patients for the single-arm trials, and from 310 to 1486 patients for the randomized trials. Efficacy endpoints evaluated for the RTOR applications included overall survival, progression-free survival, and disease-free survival for randomized controlled trials, while response rate and duration of response were the relevant endpoints for single-arm trials.

RTOR and application submission strategy

The median number of prenegotiated RTOR submission bundles was two, with a range of one to seven. The median interval between the first RTOR submission to the complete application submission was 5.7 weeks, with a range of 1.7–16.2 weeks. The applicants submitted the tabulation and analysis datasets with the first RTOR submission in 18 (90%) applications, with the remainder [2 (10%)] submitting within 4 weeks of the first RTOR submission. Tabulation datasets, also referred to as raw datasets, contain information that is directly traceable to case report forms. Analysis datasets include data that are derived with processing of the tabulation datasets and may include data from multiple tabulation datasets and other analysis datasets.

The median time from the clinical trial data cutoff to application submission was 6.1 months with a range of 2.7–15.7 months. Seventeen (85%) of the RTOR applications used the Assessment Aid (AAid), which is based on the FDA Multidisciplinary Review template and includes a company position and the FDA position in sequence, thus increasing FDA efficiency of review process (8). Six (30%) of the RTOR applications also used Project Orbis, a global collaborative review framework between FDA and international regulatory partners (9).

Review outcomes

All of the RTOR applications received approval, with majority [18 (90%)] receiving traditional approval (also known as regular approval), and two (10%) receiving accelerated approval (10). None of the RTOR applications required discussion at the Oncologic Drugs Advisory Committee.

The median time from application submission to approval was 3.3 months, with a range of 0.4–5.9 months. FDA granted the approval ahead of the PDUFA date for 18 (90%) applications, with a median time of 2.9 months (range, 0.0–5.6 months) ahead of the PDUFA date. These translate to use of approximately half of the allocated PDUFA timeline with a median of 52% (interquartile range, 32%–78%) utilization of the allocated PDUFA timeline due to early approval of the application.

When compared with non-RTOR oncology approvals (N = 60) also conducted under priority review during the same time period, applications that used RTOR showed shorter median approval times for NME (4.5 vs. 6.7 months) and supplemental applications (3.1 vs. 5.8 months; Fig. 2). Adjustment for BTD status did not affect the shorter median approval time for RTOR applications.

Figure 2.

Comparison of FDA approval times for RTOR and non-RTOR oncology applications conducted under priority review (February 2018 to April 2020). Vertical lines represent the median.

Figure 2.

Comparison of FDA approval times for RTOR and non-RTOR oncology applications conducted under priority review (February 2018 to April 2020). Vertical lines represent the median.

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The OCE's 2-year experience (February 2018 to April 2020) with RTOR across drug approvals for 20 oncology applications demonstrate that RTOR was broadly applicable across a diverse set of applications. Applications for both solid tumor and hematologic malignancy indications were included in the program and RTOR was able to be successfully applied to NMEs. While it is possible the median approval time of 3.3 months could be due to the straightforward nature of the applications, it is likely the earlier access to data (median of 5.7 weeks ahead of the full application submission) allowed for a more streamlined review process.

In addition, the OCE was able to integrate RTOR with other ongoing innovative pilot review programs including the AAid and Project Orbis. The AAid was used in 85% of the RTOR applications. The experience with the AAid improving efficiency and drug review timelines support the OCE plan to continue using the AAid with future applications.

While six (30%) of the RTOR applications also participated in Project Orbis, RTOR is only applicable to the FDA component of Project Orbis submissions because the other regulatory authorities require full application submissions (11–14). However, other regulatory authorities do not review datasets as part of application reviews. Nevertheless, the use of RTOR with Project Orbis submissions facilitates early initiation of the FDA review process.

One advantage of RTOR is the early look at the data and submission prior to official filing of the application. This could provide an opportunity to identify additional analyses to be conducted and preemptively address deficiencies with the application. This also allows for increased interaction between FDA and the applicant prior to full application submission.

Implementation of RTOR requires operational changes within the FDA and the applicant's standard procedures. Within the FDA, the staff was oriented to accept the topline results together with the datasets as the starting point for the review as opposed to waiting for the full submission. Within the applicant's organization, the applicant needed to implement steps for earlier submission of the locked datasets, with the clinical study report to closely follow. Further acceleration of review timelines could be achieved through expediting the submission timeline based on the clinical trial cut-off date. From the 20 RTOR applications evaluated, the median intervals (range) from trial cut-off date to the first RTOR submission and full application submission were 4.2 months (2.1–14.6 months) and 6.1 months (2.7–15.7 months), respectively.

A limitation with the RTOR program is the resource-intensive nature of the process. The FDA needs to ensure that there is adequate staffing and resources to support RTOR and other ongoing scientific and regulatory work. Discussions are underway on the appropriate selection criteria and the submission and review process for RTOR applications.

RTOR does not alter the review timelines that are determined on the basis of PDUFA. Although early approvals occurred with RTOR applications, this may not be feasible for all cases due to specific issues that may be identified with the application or overall workload considerations.

Currently, the RTOR program has been applied only in oncology; however, there is clearly a need for novel expedited application submission and review approaches for high priority applications, such as those eventually expected for COVID-19 prevention and treatment. OCE has demonstrated that RTOR can be successfully integrated with the FDA's existing expedited programs including Priority Review and BTD (5). These programs complemented each other, leveraging the advantages of enhanced communication of BTD, the streamlined review timeline of Priority Review, and now, the earlier access to results and data afforded by RTOR.

In conclusion, OCE reports a positive experience with the first drug approvals that used RTOR to support the application submission and review process. This innovative regulatory review process may be particularly relevant not only for oncology products, but also for other impactful products across the FDA. OCE has shared the experience and core principles of RTOR implementation with nononcology review divisions from CDER and CBER to identify which aspects of RTOR could be successfully adapted to other applications. OCE will continue offering this innovative pathway together with other the FDA and OCE programs to facilitate the regulatory review of oncology applications.

No disclosures were reported.

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