FDA’s Real-Time Oncology Review program: A model for accelerating the review of COVID-19 therapies?

The Real-Time Oncology Review pilot program has been used to expedite the approval of some oncology drugs. As AgencyIQ found, it might also be used to accelerate the review of new drugs and biologics intended to treat COVID-19. 


To contact the author of this piece, please email Kedest Tadesse (ktadesse@agencyiq.com).
To contact the editor of this piece, please email Alec Gaffney (agaffney@agencyiq.com).

 

Executive IQ Brief

  • How Things Work Now: The Real-Time Oncology Review (RTOR) pilot program has been used to expedite the drug approval review process by allowing the FDA to take review clinical data throughout the development process, and before when a company formally applies for approval.
  • What’s New: A new review program developed by the FDA for COVID-19, known as the Coronavirus Treatment Acceleration Program, borrows many expedited elements from existing FDA programs. While the program is not yet fully developed, the FDA’s Janet Woodcock has said the RTOR program may serve as a model for COVID-19 drug review.
  • What’s Next: The RTOR model could be helpful for getting products approved substantially more quickly than normal, but it is not a panacea for companies, who still face significant challenges. The FDA, too, many not find the approach as straightforward as it may hope.

Regulatory Background

Typically, the FDA takes between 8 and 12 months to review a new drug application (NDA) or biologics license application (BLA). The speed of a review depends on if the product is given standard review (10 months, plus 2 months of administrative time) or priority review (6 months, plus 2 months of administrative time). Typically the FDA prioritizes the review of drugs and biologics for high-need conditions that are life-threatening or debilitating.


The review process focuses on a substantial amount of data, including pre-clinical data (such as toxicology testing or testing in animals), top-line clinical results (such as whether the product was shown to work), and the raw clinical trial data associated with each trial participant. The evaluation of this data is extremely time-consuming, and the review process is intended to identify potential problems with the application, identify safety signals, and determine if a product should be approved and, if so, for which indications of use.


The FDA will also review supplemental NDAs and BLAs, which are used to support the approval of a new indication of use for a drug. The review of an sNDA or sBLA can be somewhat abbreviated, since the FDA and sponsor already know a significant amount about a product. 


However, the review still generally takes the standard amount of time since the FDA must review new data within a new clinical context. Some diseases may alter the effects of a drug, for example.


In recent years, the FDA has been pushed to accelerate the review of medications for patients with high levels of clinical need, and in particular those with conditions requiring rapid access to new innovations. One notable area in which this need is most evident is cancer.


In 2018, the FDA’s Oncology Center of Excellence established a pilot program known as Real-Time Oncology Review (RTOR). The goal of the program is to efficiently review applications for approval “to ensure that safe and effective treatments are available to patients as early as possible.”


A key feature of the program is the “real time” review element. Under a standard review, the FDA typically waits for an applicant to formally submit an application before it begins to review the company’s data. Under the RTOR program, the FDA will begin reviewing a prospective applicant’s data even before an application for approval is officially submitted. By communicating with a sponsor throughout the development process, the FDA is able to more efficiently and quickly review an application for approval once it is submitted. 


This allows for any deficiency to be communicated to the sponsor early-on. By the time the application is submitted for review in its entirety, sponsors are presenting data that is analyzed and organized based on the reviewer’s initial analysis of the raw data. Additionally, during the pre-review period, the FDA is able to analyze safety and efficacy data, thereby shortening the entire review time.


According to former FDA commissioner Scott Gottlieb, the RTOR program could potentially save between 10% and 30% of the reviewer’s time.


For now, participation in the RTOR pilot criteria is limited to applications that have straightforward trial designs with easy-to-interpret endpoints, and therapies that demonstrate substantial improvement over available therapy. Though the pilot program was initially geared towards sNDAs and sBLAs, it has expanded to some new molecular entities (NMEs) submitted under an NDA or BLA as well.


Several products have been approved under the RTOR program. The first approval was an sNDA filed for Kisqali (ribociclib) in mid-2018. The review was completed in 20 days once the completed sNDA was submitted. Since then, multiple sNDAs and sBLAs have been approved under the RTOR program. In 2019, the first new molecular entity (NME) NDA was approved three months earlier than the approval goal date under the RTOR program.


The program is still considered a pilot. The agency doesn’t have a definite timeline of how long the pilot will continue, but a permanent program might be underway considering the success of the program.


A general time frame for RTOR pilot program review is shown in the figure below.

An overview of the FDA’s Real-Time Oncology Review (RTOR) pilot

 

Regulatory Context

For patients, the obvious benefit of RTOR is accelerated approval of—and therefore access to—medications. As the FDA now looks to find ways to accelerate the review of treatments for COVID-19, the RTOR program may serve as a model for how the FDA approaches the review of new products.


The FDA recently established the Coronavirus Treatment Acceleration Program (CTAP), a novel program intended to use “every available method to move new treatments to patients as quickly as possible” while evaluating benefit and risk in parallel.


The program appears to borrow elements from several other of the FDA’s expedited programs, including Fast Track, Accelerated Approval, Breakthrough Therapy Designation and Priority Review.


While some elements of the program haven’t yet been established, the CTAP emphasizes rapid review. IND requests and protocols are reviewed in about a day, expanded access requests may be reviewed in just 3 hours, and the FDA says it will provide “ultra-rapid, interactive input” on companies’ development plans.

 

What’s New

As the FDA moves to expand the CTAP program in the future, it may decide to make broader use of the RTOR model to further accelerate reviews.


The real-time aspect of the review program may prove especially helpful, allowing FDA reviewers to look at data early on. While data analysis, draft reports and sections of the required documents are under preparation, the FDA reviewers will have the opportunity to analyze the subject’s raw data alongside sponsors.


An additional benefit of the program is the continuous advice the agency offers instead of the standard prescheduled approval meetings which are very limited. For instance, during the RTOR period for Kisqali, the agency had a biweekly teleconference with the sponsor. This allows direct and timely access to reviewers supporting the drug development program.


The RTOR model might therefore limits the waste of resources, including the most valuable one: Time.


In a podcast interview with the Pink Sheet last week, CDER Director Janet Woodcock said the FDA will be “watching COVID-19 trials as they unfold, much like a Real-Time Oncology Review, or like we did back in the early days of the AIDS epidemic.”


Trials would have to be complete and the database (of trial data) locked for a real-time review program to commence, but Woodcock said she believed that trial data could be collected quickly for COVID-19. She said as long as trials are large enough with a valid outcome measure, real-time review could be implemented immediately to expedite the review process.

 

What’s Next

If and when a RTOR-like program is available for COVID-19 drug developers, sponsors will have to be ready and understand the process to expedite their application review.

Real-time review does not just rely on the FDA, but rather a close collaboration between the FDA and the drug’s developer. If an FDA reviewer has a question at 10 PM on a Saturday, a company official needs to be available to take the call. Sponsors will also need to identify other potential bottlenecks, including the time it takes to develop a clinical study report sufficient for FDA review, the time it takes to assemble a formal NDA or BLA, and the establishment of manufacturing processes and capabilities.


The fastest FDA review will be for naught if the company is unable to actually manufacture the drug in sufficient quantities. The establishment of a manufacturing facility ordinarily takes years. Even the acquisition of bulk active pharmaceutical ingredients could prove challenging if countries that ordinarily make them don’t allow them to be exported.


Sponsors should discuss prospective endpoints and clinical trial designs with the FDA as early as possible. According to the FDA, it is providing ultra-rapid protocol review under CTAP. Furthermore, data collection and processes to share clinical data according to FDA’s guidelines should be planned ahead of time.


The RTOR program cuts multiple red tapes that normally exist during application review. Generally, the agency looks through an NDA or BLA for 60 days prior to accepting it for review. 


The RTOR eliminates this delay.


If the RTR-approach is used for CTAP, the FDA will be challenged in several ways. The current program model is geared toward the review of supplemental filings with simple trial designs. Many of the drugs in development for COVID would be new filings with poorly understood endpoints and messy trial designs. Many products would have new chemistry, manufacturing and controls information, which is normally excluded from the FDA’s RTOR program.


As the CTAP program evolves, expect to see the agency look to what it’s learned from the RTOR program, but don’t expect the path ahead to be seamless.

 

Key Documents and Dates

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