FDA's RTOR Program: Draft Guidance & Insights

First launched in February 2018 by the FDA’s Oncology Center of Excellence, the Real-Time Oncology Review (RTOR) program is intended to streamline the review process for oncology drug applications. The idea is that submitting top-line safety and efficacy data from pivotal clinical trials ahead of time will allow FDA reviewers to identify any issues or deficiencies for the sponsor to address before the application is submitted in its entirety. This early engagement with the FDA, and the increased communication and collaboration, is anticipated to improve the efficiency of the review. In its initial iteration, the program was limited to supplemental applications, but in December 2018 it was expanded to include original applications for new molecular entities (NMEs) as well. With this pilot program now in its fifth year, in July the FDA issued draft guidance for industry.¹ This article summarizes the new guidance and reviews the performance of the RTOR program thus far.

Eligibility For RTOR

According to the guidance, there are three criteria a submission must fulfill to qualify for the RTOR program:

1. The drug is likely to provide a meaningful benefit over existing therapy or has been granted or qualifies for an expedited program.
2. The design of the study is straightforward.
3. The clinical endpoints of the study are easily interpretable (e.g., overall survival or response rate).

Some products, such as cell or gene therapies, may not be suitable for the RTOR program even if they meet these criteria, due to the complexity of the manufacturing or product characteristics.

RTOR Process

Following database lock and availability of top-line results for the pivotal study, the sponsor may send a request to participate in the RTOR program via email to their FDA regulatory project manager. The request should include the top-line results, a written justification outlining their eligibility for the RTOR program, and a proposed timeline for submission. The FDA will notify the sponsor of their decision within 20 days.

If accepted, the FDA may schedule a teleconference with the sponsor to discuss the RTOR plan and come to agreement on the timeline for submission of the components of the application. An important distinction of RTOR from Rolling Review is that the latter requires complete modules to be submitted prior to the full application. In contrast, the RTOR program allows for components of individual modules to be submitted. The FDA recommends a maximum of three partial and one final submission, for a total of four separate submissions to complete the application. The Prescription Drug User Fee Act (PDUFA) fee is due at the time the first component is submitted. Once the final component is submitted, the PDUFA clock officially starts.

The FDA also recommends including with the submission an Assessment Aid.² The Assessment Aid program is another pilot project of the FDA’s Oncology Center of Excellence, through which the sponsor may complete a template to assist the FDA reviewers in their assessment of the application.

Historical Performance Of The RTOR Program

Using the FDA’s Oncology (Cancer)/Hematologic Malignancies Approval Notifications website³ as a data source, a total of 58 drugs were determined to have been approved under the RTOR program as of this writing. An analysis of the number of approvals by year indicates a steady increase from the program’s inception in 2018 through 2021 (see Figure 1).

Figure 1. Approvals using the RTOR program, by year.

Fifteen of the 58 approvals (25.9%) were original applications for NMEs; the remaining 43 (74.1%) were supplemental applications. All but one of the applications (57/58, 98.3%) were confirmed to have used at least one expedited program.

While the RTOR program makes no promises with respect to speed of review, the hope that participation will lead to a faster approval has attracted many sponsors. This hope is not unfounded.

The first approval using the RTOR program was a supplemental New Drug Application (sNDA) for ribociclib (KISQALI, Novartis Pharmaceuticals Corporation) in combination with an aromatase inhibitor for pre/perimenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer as initial endocrine-based therapy.⁴ With submission of the final component of the application on June 28, 2018,⁵ the review was completed in an impressive 20 days, and approval occurred on July 18, 2018.

The record for quickest review of a supplemental application belongs to brentuximab vedotin (ADCETRIS, Seattle Genetics Inc.), approved Nov. 16, 2018, in combination with chemotherapy for previously untreated systemic anaplastic large cell lymphoma or other CD30-expressing peripheral T-cell lymphomas.⁶ The submission of the supplemental Biologics License Application (sBLA) was completed on Nov. 5, 2018,⁷ just 11 days prior.

For an original application for an NME, the most expeditious review was for asparaginase erwinia chrysanthemi (recombinant-rywn) (RYLAZE, Jazz Pharmaceuticals, Inc.), approved June 30, 2021 as a component of a multi-agent chemotherapeutic regimen for the treatment of acute lymphoblastic leukemia and lymphoblastic lymphoma in adult and pediatric patients 1 month or older who have developed hypersensitivity to E. coli-derived asparaginase.⁸ The final submission for the BLA was made on April 30, 2021,⁹ 61 days prior.

But while many of the drugs approved using this program have achieved rapid review times, there are a few outliers. Notably, dostarlimab-gxly (JEMPERLI, GlaxoSmithKline LLC), approved April 22, 2021, for adult patients with mismatch repair deficient recurrent or advanced endometrial cancer that has progressed on or following a prior platinum-containing regimen,¹⁰ submitted the final component of the BLA on Dec. 19, 2019¹¹ – 490 days earlier!

Overall, an analysis conducted by FDA authors evaluating the approval times for oncology applications who used the RTOR program vs. those that didn’t over the course of the first year the program was implemented found that using RTOR resulted in shorter median review times. This was true for both original applications for NMEs and supplemental applications.¹² If a sponsor has an eligible oncology drug application and the resources available to rapidly assemble and submit the components, taking advantage of the RTOR program is an option likely to result in an early action date.

References

1. United States Food and Drug Administration. Real-Time Oncology Review (RTOR) Guidance for Industry. July 2022. https://www.fda.gov/media/160186/download
2. United States Food and Drug Administration. Assessment Aid. https://www.fda.gov/about-fda/oncology-center-excellence/assessment-aid  
3. United States Food and Drug Administration. Oncology (Cancer)/Hematologic Malignancies Approval Notifications. https://www.fda.gov/drugs/resources-information-approved-drugs/oncology-cancer-hematologic-malignancies-approval-notifications
4. United States Food and Drug Administration. FDA expands ribociclib indication in HR-positive, HER2-negative advanced or metastatic breast cancer. July 18, 2018. https://wayback.archive-it.org/7993/20201222065155/https://www.fda.gov/drugs/resources-information-approved-drugs/fda-expands-ribociclib-indication-hr-positive-her2-negative-advanced-or-metastatic-breast-cancer
5. United States Food and Drug Administration. Approval letter for KISQALI® (ribociclib) sNDA. July 18, 2018. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2018/209092Orig1s001ltr.pdf
6. United States Food and Drug Administration. FDA approves brentuximab vedotin for previously untreated sALCL and CD30-expressing PTCL. November 16, 2018. https://wayback.archive-it.org/7993/20201222064804/https://www.fda.gov/drugs/fda-approves-brentuximab-vedotin-previously-untreated-salcl-and-cd30-expressing-ptcl
7. United States Food and Drug Administration. Approval letter for ADCETRIS® (brentuximab vedotin) sBLA. November 16, 2018. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2018/125388Orig1s099ltr.pdf
8. United States Food and Drug Administration. FDA approves asparaginase erwinia chrysanthemi (recombinant) for leukemia and lymphoma. June 30, 2021. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-asparaginase-erwinia-chrysanthemi-recombinant-leukemia-and-lymphoma
9. United States Food and Drug Administration. Approval letter for RYLAZE (asparaginase erwinia chrysanthemi (recombinant)-rywn) BLA. June 30, 2021. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2021/761179Orig1s000ltr.pdf
10. United States Food and Drug Administration. FDA grants accelerated approval to dostarlimab-gxly for dMMR endometrial cancer. April 22, 2021. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-dostarlimab-gxly-dmmr-endometrial-cancer
11. United States Food and Drug Administration. Approval letter for JEMPERLI (dostarlimab-gxly) BLA. April 22, 2021. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2021/761174Orig1s000ltr.pdf
12. de Claro RA, Gao JJ, Kim T, Kluetz PG, Theoret MR, Beaver JA, Pazdur R. U.S. Food and Drug Administration: Initial Experience with the Real-Time Oncology Review Program. Clin Cancer Res. 2021 Jan 1;27(1):11-14.

About The Author:

Marjorie Zettler, Ph.D., MPH is director of clinical science at Regor Pharmaceuticals, Inc. An industry veteran with nearly two decades’ experience in the pharma and healthcare sector, her work has focused on clinical research, drug development, and regulatory strategy. She has published more than 100 abstracts, manuscripts, and patents.