Industry groups: Expand FDA’s RTOR guidance to cell and gene therapies

Regulatory NewsRegulatory News | 27 September 2022 |  By 

Stakeholders commenting on the US Food and Drug Administration (FDA) draft guidance with recommendations for applicants submitting New Drug Applications (NDA) and Biologic License Applications (BLA) for Real-Time Oncology Review (RTOR) want more clarity on how the guidance applies to cell and gene therapies and have asked the agency to align the draft guidance with what appears on the RTOR website.
 
FDA’s draft guidance, released in July 2022, is intended to help industry identify oncology drugs that may qualify for RTOR, which would result in a head-start review by the agency and may decrease review time for sponsors. When RTOR was launched by the FDA Oncology Center of Excellence (OCE) in 2018, the program only included supplemental oncology drug applications, but now encompasses original oncology NDAs for new molecular entities and original oncology BLAs. (RELATED: FDA explains the ins and outs of real-time oncology review program in new guidance, Regulatory Focus 26 July 2022)
 
“The OCE developed RTOR to facilitate earlier submission of critical efficacy and safety data to initiate FDA’s evaluation of the application, whereby components of individual modules (e.g., parts of the clinical module, etc.) may be submitted at separate times,” FDA wrote in the draft guidance. “RTOR is different than the existing mechanisms for rolling review in which, generally, complete modules (e.g., the complete clinical module) are submitted prior to a complete application submission.”
 
Oncology drugs that qualify for RTOR if they are likely to show “substantial improvement” compared with other treatments and qualify for FDA’s expedited programs and have been identified by OCE and the review division as having a straightforward study design and easily interpreted clinical endpoints such as overall survival and response rates.
 
Applicants can apply for RTOR once top-line results for the trial are available and the database has been locked, FDA said. The process involves writing to the regulatory project manager and to the Investigational New Drug Application (IND) with the results and justification for the candidate meeting RTOR requirements along with a proposed timeline for submission of the rest of the RTOR application components. FDA said a response will typically be issued by email within 20 days of receiving the RTOR application.
 
Should RTOR apply to cell and gene therapies?
 
The Alliance for Regenerative Medicine (ARM) raised several questions in their comments to FDA, noting that the draft guidance appears to apply to some, but not all biological products. The guidance specifies that “for certain biological products, such as cell and gene therapies, for which complex manufacturing and product characteristics need to be considered in evaluating the safety and efficacy of the product,” and recommended “discussion of whether the product is suitable for RTOR take place with the appropriate review division.”
 
“ARM members encourage the Agency not to create a different standard for cell and gene therapies (CGT) but instead consider, and provide advice on, the extent of [chemistry, manufacturing, and controls] CMC information that will need to be available at each of the partial submissions allowed in RTOR program to allow it to be routinely suitable to CGTs,” they wrote.
 
Pfizer, meanwhile, took FDA’s comments in the draft guidance to mean the agency was open to a discussion on whether RTOR should apply to CGTs.
 
“Pfizer is encouraged that FDA is directing sponsors to discuss the potential for using RTOR for cell and gene therapies with the appropriate review division,” they said. “Pfizer supports the use of RTOR on these new and promising areas of drug development where it has the potential to streamline future reviews for the benefits of patients.”
 
The Pharmaceutical Research and Manufacturers of America (PhRMA) also weighed in on this issue in their comment, noting they also support applying RTOR to CGT products.
 
“Given the demonstrated potential for RTOR to expedite patient access to effective therapies, and that substantial experience has been accumulated by sponsors and the Agency since RTOR was first introduced in 2018, PhRMA now urges FDA to apply the program to more oncology products, where appropriate. Specifically, human cell and tissue products reviewed by CBER, as well as products utilizing digital health technologies (DHTs) in support of their applications, should also be considered for the RTOR program.”
 
Aligning RTOR guidance with OCE website
 
Stakeholder comments also pointed out that the FDA OCE website for RTOR contains different information on processes than are present in the draft guidance. ARM, Pfizer and PhRMA all recommended a figure from the website depicting an example overall RTOR timeline be included in the guidance, and that FDA should include any request table or template the agency has been sending sponsors as an appendix to the guidance.
 
While FDA notes on the RTOR website that they prefer use of the OCE Assessment Aid for RTOR, it does not appear in the draft guidance, the commenters said.
 
“PhRMA recommends that the OCE update the guidance to clarify expectations around the use of the Assessment Aid and include the timepoint in the RTOR process that would be most useful for the sponsor to submit the Assessment Aid,” PhRMA wrote.
 
Clarifying processes for RTOR
 
All three commenters had clarifying questions about varying parts of the RTOR process. ARM noted that it is currently unclear what information is currently needed for the first partial submission, while acknowledging that this may be a moving target based on timelines for deliverables.
 
“[I]t would be helpful for OCE to specify in the guidance the key information that is needed to facilitate the review, particularly what information is most valuable to reviewers in the initial submission, so Sponsors can plan accordingly,” they said.
 
ARM, Pfizer and PhRMA also requested more information on when certain CMC information could be submitted throughout the review process but differed in their recommendations for how FDA should proceed. While ARM and PhRMA recommended CMC information be submitted in parts and manufacturing, testing and facilities be included in the first submission, Pfizer recommended leaving CMC components in the Assessment Aid for the last wave of CMC content submissions.

 

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