Rolling Review, Real time oncology review (RTOR), and Split real time application review (STAR) Program

For New Drug Application (NDA) and Biological License Application (BLA), the usual process is to submit the entire package with different modules at the same time. The submission package will include the quality, CMC, non-clinical study reports, and clinical study reports,... However, there are processes by which the sponsor can submit the submission package piece by piece: rolling review, real-time oncology review, and split real-time application review (STAR) program.

Rolling Review

Rolling review was one of the benefits for drug products with Fast Track Designation. According to FDA's website "Fast Track" 

A drug that receives Fast Track designation is eligible for some or all of the following:

More frequent meetings with the  FDA to discuss the drug's development plan and ensure the collection of appropriate data needed to support drug approval

More frequent written communication from FDA about such things as the design of the proposed clinical trials and use of biomarkers

Eligibility for Accelerated Approval and Priority Review, if relevant criteria are met

Rolling Review, which means that a drug company can submit completed sections of its Biologic License Application (BLA) or New Drug Application (NDA) for review by FDA, rather than waiting until every section of the NDA is completed before the entire application can be reviewed. BLA or NDA review usually does not begin until the drug company has submitted the entire application to the FDA

Fast Track Designation was one of the expedited programs described in FDA's guidance "Expedited Programs for Serious Conditions – Drugs and Biologics". Other expedited programs are breakthrough therapy designation, accelerated approval, and priority review designation. In FDA's guidance, the Fast Track Designation contains the benefit of submission of portions of an application (Rolling Review): 

Here are rolling review examples: earlier this month, Iveric Bio Announces Submission of First Part of NDA for Rolling Review of Avacincaptad Pegol for the Treatment of Geographic Atrophy; in September, 2022, Vertex and CRISPR Therapeutics Announce Global exa-cel Regulatory Submissions for Sickle Cell Disease and Beta Thalassemia

Real-Time Oncology Review (RTOR) Program

For oncology products, FDA's The Oncology Center of Excellence has a program called "real-time oncology review (RTOR)". RTOR facilitates earlier submission of topline efficacy and safety results, prior to the submission of the complete application, to support an earlier start to the FDA’s evaluation of the application. FDA's website "Real-Time Oncology Review" described the details about RTOR program. 

Some companies have utilized this program in hope of expediting their submission/review process. 

In a press release "SpringWorks Therapeutics Announces Data from Phase 3 DeFi Trial Evaluating Nirogacestat in Adult Patients with Progressing Desmoid Tumors at the European Society for Medical Oncology (ESMO) Congress 2022", it stated that their Nirogacestat for R/R desmoid tumors will be filed through real-time oncology review (RTOR) program.

Nirogacestat has received Orphan Drug Designation from the U.S. Food and Drug Administration (FDA) for the treatment of desmoid tumors and from the European Commission for the treatment of soft tissue sarcoma. The FDA also granted Fast Track and Breakthrough Therapy Designations for the treatment of adult patients with progressive, unresectable, recurrent or refractory desmoid tumors or deep fibromatosis. SpringWorks plans to submit a New Drug Application (NDA) to the FDA in the second half of 2022, which will be submitted for review under the FDA’s Real-Time Oncology Review (RTOR) program.

Amgen's Sotorasib was approved by FDA for the first and only targeted treatment for patients with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer. The Sotorasib's BLA submission was through RTOR:

"In the U.S., LUMAKRAS was reviewed by the FDA under its Real-Time Oncology Review (RTOR), a pilot program that aims to explore a more efficient review process that ensures safe and effective treatments are made available to patients as early as possible."

 An article in Life Science Leader magazine "FDA's RTOR Program: Draft Guidance & Insights" provides a good summary of the RTOR program.

Split Real-Time Application Review (STAR)

STAR program builds off the Oncology Center of Excellence’s Real-Time Oncology Review (RTOR) program, In the newly passed PDUFA VII for the years 2023 through 2027, a new program called Split real-time application review (STAR) was proposed. According to PDUFA reauthorization performance goal and procedures fiscal years 2023 through 2027, the STAR program was described as the following: 

D. SPLIT REAL TIME APPLICATION REVIEW (STAR) PILOT PROGRAM

FDA will establish a STAR pilot program, which has the goal of shortening the time from the date of complete submission to the action date, in order to allow earlier patient access to therapies that address an unmet medical need. The STAR pilot program will apply to efficacy supplements across all therapeutic areas and review disciplines that meet specific criteria. Accepted STAR applications will be submitted in a “split” fashion, specifically in two parts (with the components submitted approximately 2 months apart).

1. Scope: The STAR program will seek to expedite patient access to novel uses for existing therapies by supporting initiation of review earlier than would otherwise occur and therefore allowing earlier approval for qualified efficacy supplements. This program will apply across all therapeutic areas and review disciplines for applications that meet specific criteria. An application will be considered eligible for STAR if each of the following criteria are met: a. Clinical evidence from adequate and well-controlled investigation(s) indicates that the drug may demonstrate substantial improvement on a clinically relevant endpoint(s) over available therapies. Breakthrough Therapy Designation (BTD) or Regenerative Medicine Advanced Therapy Designation (RMAT) is not required, but above criteria must be met. b. The application is for a drug intended to treat a serious condition with an unmet medical need. c. No aspect of the submission is likely to require a longer review time (e.g., requirement for new REMS, etc.). d. There is no chemistry, manufacturing, or control information that would require a foreign manufacturing site inspection (i.e., domestic site inspections may be allowed if it does not affect the expedited timeframe).

FDA's website "Split Real-Time Application Review (STAR)" described how the STAR program should be operated.

Are data listings for clinical study reports still needed in the era of CDISC standard data sets (SDTM)?

Traditionally, all data fields that are collected in clinical trials, will be listed in so-called 'data listings'. The data listings are the basis for the summary and analysis tables or figures, and all together, tables, listings, and figures (TLFs) form the basis for the clinical study report (CSR). According to the ICH E3 "Structure and Content of Clinical Study Reports", these data listings are included in the CSR section 16.2 "Patient data listings". 

Now that the CDISC standard has become a mandate for regulatory submission of the clinical trial data, the data sets submitted to the regulatory agencies will follow the same standards (data structure, data set name, variable names,...). This will enable the regulatory reviewers to use the software (the data visualization software such as JMP-Clinical) to visualize and review the data and perform the data mining activities. Logical thinking is that in the era of CDISC standard data sets (SDTM - study data tabulation model), the data listings become obsolete and redundant. Some sponsors argue that there is no need to generate the data listings if the submitted data sets are in SDTM format. 

In a presentation "Alternatives to Static Data Listings for Clinical Study Reports" in a CDISC virtual conference, the presenters argued:

"Sponsors often create voluminous static listings for Clinical Study Reports (CSRs) and submissions, and possibly for internal use to review safety information.  This is likely due to the perception that they are required and/or lack of knowledge of various alternatives.   However, there are other ways of viewing clinical study safety data which can provide an improved user experience, and are made possible by standard structures for such data, such as the Study Data Tabulation Model (SDTM). The purpose of this paper is to explore some alternatives to providing a complete set of static listings and make a case for sponsors to begin considering these alternatives."

On Pinnacle 21's website, there was a blog article "FDA Final Guidance Webinar Q&A":

28. With the advent of a new "misc folder" instead of listings do you think that FDA is getting away from generating listings for each study? It seems that the data sets (SEND, SDTM, and ADaM) would stand alone to support any listings.

Answer: Once the standards requirements are in effect, the idea would be that listings would be replaced by the SDTM tabulations data, so yes.

It seems that FDA is ok not to receive the data listings since the CDISC-compliant data sets are submitted. However, it is still the sponsor's risk to take if data listings are not generated and not included in the CSR. The vast majority of the sponsors are still generating the data listings for the CSR and including the data listings in the submission even in the era of CDISC standard data sets. 

In deciding if the data listings need to be generated for CSR and submission, the sponsor needs to consider: 

• The industry trend. Is it still the industry standard to generate the data listings even after CDISC compliant data sets are submitted?
• Is there an official guideline indicating that the data listings should not be generated? 
• How to handle CSR section 16.2 according to ICH E3 regarding patient data listings if data listings are not generated? 
• Data listings may be used for internal reviews (medical review, medical writing, Quality Control review,…) even though FDA reviewers may not need the data listings because they have specific tools to review the SDTM data sets
• Data listings may be needed if the submissions are needed for other regulatory agencies beyond the FDA.
• Not all reviewers have the tools or can effectively use the tools to review the electronic data sets. Some reviewers still rely on the data listings to review the individual subject-level data. 

In the era of CDISC standards, more effort was spent on SDTM and ADaM data set programming. Once the SDTM and ADaM data sets are generated and the raw data sets are mapped to the standardized SDTM data sets, generating data listings is not so complicated. 

Are we moving away from data listings now that the standard data sets (such as CDISC-compliant SDTM and ADaM data sets) are mandated by FDA?

After a clinical trial is concluded, the statistical group (statisticians and statistical programmers) will generate the tables, listings, and figures (TLFs in short) for the clinical study report (CSR). If the clinical trial results are good, the CSR including the TLFs and the data sets where the TLFs are generated from will be submitted to the regulatory authorities (such as FDA) for marketing authorization application (such as new drug application (NDA) and biological license application (BLA). 

From the statistical standpoint, the clinical trial is a process to collect the data (demographic, efficacy, and safety). The data sets we collected will be converted and mapped to the standardized format according to the CDISC standards - SDTM for tabulation data sets and ADaM for analysis data sets. The standardized data sets are then used for generating the tables, listings, and figures (may also be called the post-text TLFs). The post-text TLFs will be the building block for constructing the CSRs. 

The data listings are required as part of the CSRs and post-text listings are included in the CSRs as appendices. As specified in ICH E3 "STRUCTURE AND CONTENT OF CLINICAL STUDY REPORTS", data listings will be organized according to the sections/numbers below: 

A data listing will be looking like the below with a listing of adverse events as an example (the mock-up shell). Notice that the listing for adverse events is numbered as Listing 16.2.7 corresponding to the section number indicated in ICH E3 (above).

With the FDA's mandate for submission of the standardized data sets, the CDISC standard tabulation data set is SDTM (study data tabulation model), the natural question is if the data listings are still needed. The data listings are just the simple display of the SDTM data set (or ADaM data set) with format/layout beautified. Some sponsors have moved to the direction of not generating the formal data listings and they think that the CDISC-compliant data sets will be sufficient to replace the data listings. 

According to an FDA Final Guidance Webinar Q&A at Pinnacle21 website, the response indicated that the data listings would be replaced by the standard data sets. 

28: With the advent of a new “misc folder” instead of listings do you think that FDA is getting away from generating listings for each study? It seems that the datasets (SEND, SDTM, and ADaM) would stand alone to support any listings.

Once the standards requirements are in effect, the idea would be that listings would be replaced by the SDTM tabulations data, so yes.

The Final FDA Guidance on Standardized Study Data was initially published December 17, 2014 and has subsequently been revised several times. The FDA Binding Guidance requires Sponsors whose studies start after December 17, 2016 must submit data in FDA-supported formats listed in the FDA Data Standards Catalog. The FDA Data Standards Catalog specifies the use of CDISC standards such as SDTM, ADaM, and Define-XML as well as Controlled Terminology.

FDA has organized or participated in multiple webinars to emphasize the criticality of submitting the data sets in standardized formation, however, there is no subsequent mention about the standardized data sets replacing the data listings. 

I did an informal survey and asked the statisticians and statistical programmers working in other pharmaceutical companies and CROs, almost all responses were that they continue to generate data listings and have no plan to stop generating data listings even though they have been fully compliant with the CDISC data standards for their clinical trials.

Even though the CDISC compliant data sets make the data listings redundant and unnecessary, stopping generating the data listings entirely is a risky approach at this point. The data listings should still be generated until we see FDA's guidance indicating otherwise or until the ICH E3 is revised to indicate that the data listings can be replaced by the standardized data sets. 

Some links to this topic: 

• FDA website: Study Data Standards Resources
• FDA website: Study Data for Submission to CDER and CBER
• FDA Webinar: The FDA Study Data Technical Conformance Guide v4.4 - Nov 22, 2019
• Study Data Technical Conformance Guide - FDACDER Small Business and Industry Assistance (CDER SBIA) Webinar - Study Data Standards in eCTD: What You Need to Know about the New Technical Rejection Criteria - October 12, 2016
• Duke Margolis Center for Health Policy in collaboration with FDA organized a public workshop: Advancing the Development and Implementation of Analysis Data Standard: Key Challenges and Opportunities: