Real-Time Oncology 
Review (RTOR)  
Guidance for Industry 
 
 
 
 
    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Oncology Center of Excellence (OCE) 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
November 2023 
Administrative/Procedural 
   
Real-Time Oncology 
Review (RTOR) 
Guidance for Industry 
 
Additional copies are available from: 
 
Office of Communications, Division of Drug Information  
Center for Drug Evaluation and Research 
Food and Drug Administration 
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Silver Spring, MD 20993-0002  
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353 
Email: druginfo@fda.hhs.gov  
https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs  
 
and/or 
 
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Center for Biologics Evaluation and Research 
 Food and Drug Administration 
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Silver Spring, MD 20993-0002 
Phone: 800-835-4709 or 240-402-8010 
Email: ocod@fda.hhs.gov 
https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-information-biologics/biologics-
guidances     
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
 Oncology Center of Excellence (OCE) 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
November 2023 
Administrative/Procedural 
   
TABLE OF CONTENTS 
 
 
I.  INTRODUCTION..................................................................................................1 
II.  BACKGROUND ....................................................................................................2 
III.  ELIGIBLE APPLICATIONS ...............................................................................2 
IV.   RTOR PROCESS...................................................................................................3 
V.   ADDITIONAL REGULATORY CONSIDERATIONS ....................................5 
 
 
  Contains Nonbinding Recommendations 
 
Real-Time Oncology Review (RTOR) 
Guidance for Industry1 
 
 
This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on 
this topic. It does not establish any rights for any person and is not binding on FDA or the public. You can 
use an alternative approach if it satisfies the requirements of the applicable statutes and regulations. To 
discuss an alternative approach, contact the FDA staff responsible for this guidance as listed on the title 
page. 
 
 
 
 
I.  INTRODUCTION  
 
The purpose of this guidance is to provide recommendations to applicants on the process for 
submission of selected new drug applications (NDAs) and biologics license applications (BLAs) 
with oncology indications for review under Real-Time Oncology Review (RTOR).2  
 
This guidance does not address FDAs expedited programs such as the Fast Track Designation, 
Breakthrough Therapy Designation, or Priority Review Designation. Additional information on 
these expedited programs can be found in the guidance for industry Expedited Programs for 
Serious Conditions  Drugs and Biologics (May 2014).3 RTOR is separate from the Split Time 
Application Review (STAR) pilot program which was established under the Prescription Drug 
User Fee Act (PDUFA) VII commitments.4 
 
In general, FDAs guidance documents do not establish legally enforceable responsibilities. 
Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
as recommendations, unless specific regulatory or statutory requirements are cited. The use of 
the word should in Agency guidances means that something is suggested or recommended, but 
not required. 
 
 
 
 
1 This guidance has been prepared by the Oncology Center of Excellence (OCE) in consultation with the Office of 
Oncologic Diseases in the Center for Drug Evaluation and Research (CDER), and Center for Biologics Evaluation 
and Research (CBER) at the Food and Drug Administration.  
 
2 Real-Time Oncology Review Program: https://www.fda.gov/about-fda/oncology-center-excellence/real-time-
oncology-review-pilot-program.  
 
3 We update guidances periodically. For the most recent version of a guidance, check the FDA guidance web page at 
https://www.fda.gov/RegulatoryInformation/Guidances/default.htm.  
 
4 Split Real Time Application Review: https://www.fda.gov/drugs/development-resources/split-real-time-
application-review-star.    
1  Contains Nonbinding Recommendations 
 
II.  BACKGROUND 
 
The FDA Oncology Center of Excellence (OCE), in collaboration with the Office of Oncologic 
Diseases (OOD), commenced RTOR in February 2018 to facilitate earlier submission of top-line 
results (i.e., efficacy and safety results from clinical studies before the study report is completed) 
and datasets, after database lock, to support an earlier start to the FDA application review.5 
Initially, only supplemental oncology drug6 applications (to add new indications, dosing 
regimens, or other clinical information to the prescribing information) were reviewed under 
RTOR. The program was expanded later to include select original oncology NDAs for new 
molecular entities (NMEs) submitted under section 505(b) of the Federal Food, Drug, and 
Cosmetic Act and original oncology BLAs submitted under section 351(a) of the Public Health 
Service Act. 
 
In a typical FDA drug review process, efficacy and safety data are submitted at the same time as 
other elements of a drug application (e.g., administrative information, summary documents, 
clinical study reports, manufacturing information, and nonclinical study reports, etc.) for a 
complete application. However, the process of assembling a drug application for submission 
usually takes at least several months. The OCE developed RTOR to facilitate earlier submission 
of critical efficacy and safety data to initiate FDAs evaluation of the application, whereby 
components of individual modules (e.g., parts of the clinical module, etc.) may be submitted at 
separate times. RTOR is different from the existing mechanisms for submission of portions of an 
application for rolling review in which, generally, complete modules (e.g., the complete clinical 
module) are submitted prior to a complete application submission. The intent of RTOR is to 
provide FDA reviewers earlier access to data, to identify data quality and potential review issues, 
and to potentially enable early feedback to the applicant, which can allow for a more streamlined 
and efficient review process.  
 
RTOR does not alter the review performance goals and timelines associated with the 
applications, including as described in the PDUFA. Although early approvals have occurred with 
applications included in RTOR, this may not be feasible for all applications due to specific issues 
that may be identified with the application or overall workload considerations. Acceptance into 
RTOR does not guarantee or influence approval of the application, which is subject to the same 
statutory and regulatory requirements for approval as applications that are not included in RTOR. 
Participation by the applicant in this program is voluntary. If at any point FDA determines 
participation in the program is no longer appropriate, FDA may rescind acceptance and instruct 
the applicant to use routine submission procedures for their application. 
 
 
III.  ELIGIBLE APPLICATIONS 
 
To be considered for RTOR, submissions should demonstrate the following:  
 
5 de Claro, RA, JJ Gao, T Kim, PG Kluetz, MR Theoret, JA Beaver, R Pazdur, 2021, U.S. Food and Drug 
Administration: Initial Experience with the Real-Time Oncology Review Program, Clin Cancer Res, 27 (1): 11-14.  
 
6 For the purposes of this guidance, all references to drugs include both human drugs and therapeutic biological 
products unless otherwise specified. 
2  Contains Nonbinding Recommendations 
 
  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.7   
 
  Easily interpreted clinical trial endpoints (e.g., overall survival, response rates), as 
determined by the review division and OCE. 
 
  No aspect of the submission is likely to require a longer review time (e.g., 
requirement for new REMS, advisory committee, etc.). 
 
RTOR involves early engagement with the applicant to discuss the submission timelines for 
RTOR components and the full application submission. To determine eligibility for RTOR, FDA 
would need the top-line 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.  
 
 
IV.   RTOR PROCESS 
 
  At the time top-line results of a pivotal trial(s) are available and the database has been 
locked, an applicant may apply for review under RTOR by submitting a request to the 
Investigational New Drug Application (IND). The applicant should include their top-line 
results and submit RTOR Request information8, which includes information such as the 
justification explaining how their application demonstrates that it is appropriate for 
RTOR, as described in Section III above and a proposed timeline of when it will submit 
the various components of the RTOR application (listed below). The review division 
director/deputy director, with input from the review team (including reviewers, team 
leaders, and management from all relevant review disciplines), will decide whether the 
application will be selected for RTOR. This decision will generally be made within 20 
business days of receipt of the request and communicated to the applicant via email.  
 
  If the application is not accepted into RTOR, the applicant should follow routine 
application submission procedures. 
 
  Once an application is selected, a teleconference with the applicant may be scheduled if 
necessary (generally within 20 business days). The OOD clinical division director/deputy 
director, the review team, and OCE staff may participate in this meeting. FDA and the 
applicant will discuss the plan for RTOR and reach tentative agreement on proposed 
submission timelines for the drug application.  
 
 
7 RTOR may not be suitable 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. 
For these types of products, we recommend that a discussion of whether the product is suitable for RTOR take place 
with the appropriate review division. 
 
8 Applicants should contact their assigned Regulatory Project Manager (RPM) for information that should be 
submitted in an RTOR request.  
3  Contains Nonbinding Recommendations 
 
  The applicant should submit the following items to their marketing application per the 
agreed-upon timeline:9  
 
  Top-line efficacy/safety tables/figures   
o
 
  Complete Study Data Tabulation Model (SDTM)10 dataset package  
o
 
  Complete Analysis Data Model (ADaM) datasets for key efficacy and safety 
o
tables/figures for pivotal study (see OOD data specifications11 for requested 
format of safety datasets)  
 
  The protocol and amendments (a list of major changes for each amendment), 
o
Statistical Analysis Plan (SAP), and Data Monitoring Committee (DMC) charter 
and DMC minutes  
 
  Statistical (e.g., SAS) programs  
o
 
  Proposed labeling  
o
 
  Summary of data and rationale supporting dose and dosing regimen selection 
o
(including key population pharmacokinetics (PK), physiologically-based (PB)/PK 
and exposure-response reports, analyses programs, and datasets) 
 
  Summary of clinical pharmacology studies and datasets supporting the 
o
conclusions 
 
  Key results, analysis, and datasets for other disciplines (e.g., clinical 
o
pharmacology), if applicable  
 
  Final study reports of all supportive studies, including pharmacology and 
o
toxicology studies  
 
  Case report forms (CRFs) as required by applicable regulations12   
o
 
  All Chemistry, Manufacturing, and Controls (CMC) information, if appropriate, 
o
including list of all manufacturing, testing and critical intermediate facilities with 
addresses and FDA Establishment Identifier (FEI) numbers other than stability 
 
9 For an example RTOR submission timeline, refer to the RTOR website at https://www.fda.gov/about-
fda/oncology-center-excellence/real-time-oncology-review-pilot-program.   
 
10 FDA Study Data Standards Resources: https://www.fda.gov/industry/fda-resources-data-standards/study-data-
standards-resources. 
  
11 OOD Data Specifications: https://www.fda.gov/media/133252/download. 
 
12 See 21 CFR 314.50. 
4  Contains Nonbinding Recommendations 
 
data for registration batches (if not available) for drug substance(s) and drug 
product   
 
  Pediatric study plan (as required) 
o
 
  Request for proprietary name review (as required) 
o
 
  Final clinical study report(s) 
o
 
  Bioresearch monitoring (BIMO) information (as applicable)13 
o
 
  Other documents as necessary, e.g., for Modules 1, 2, 4, and 5  
o
 
  In general, FDA recommends submitting these items in a maximum of three 
presubmissions and a final submission.    
 
  During the pre-NDA/BLA meeting14 to discuss the proposed application, FDA may share 
preliminary key review questions or issues and critical analyses needed. If FDA requests 
additional analyses, the applicant may submit them before or at the time of submission of 
the complete marketing application. In some cases, if FDA agrees, the applicant may 
submit the requested additional analyses after the marketing application is submitted. 
These discussions may be documented in the meeting minutes under the section, 
Agreement of a Complete Application for NDA NMEs or original 351(a) BLAs. For 
supplemental applications, RPMs may capture agreements discussed under Additional 
Items Discussed or under discussion of specific questions as appropriate in the official 
meeting minutes. 
 
  When FDA receives the final component, the application is considered complete, and the 
review clock will start.  
 
 
V.   ADDITIONAL REGULATORY CONSIDERATIONS 
 
As noted above, the applicant should submit RTOR items listed in Section IV as presubmissions 
to the NDA or 351(a) BLA. Within the cover letter of the presubmission, the subject line should 
be identified as: PRESUBMISSION FOR [INSERT INDICATION] [CHOOSE: 
ORIGINAL APPLICATION OR EFFICACY SUPPLEMENT] WITH [INSERT TYPE OF 
INFORMATION SUBMITTED, e.g., CLINICAL/STATISTICS] INFORMATION FOR 
REAL-TIME ONCOLOGY REVIEW (RTOR). In Box 21 of Form FDA 356h, the applicant 
 
13 For the content and format of this information, see the draft guidance for industry Standaridized Format for 
Electronic Submission of NDA and BLA Content for the Planning of Bioresearch Monitoring (BIMO) Inspections 
for CDER Submissions (February 2018). When final, this guidance will represent the FDAs current thinking on this 
topic.  
 
14 See the draft guidance for industry Formal Meetings Between the FDA and Sponsors or Applicants of PDUFA 
Products (September 2023). When final, this guidance will represent the FDAs current thinking on this topic. 
5  Contains Nonbinding Recommendations 
 
should identify the submission as original or efficacy supplement and in Box 22, the applicant 
should indicate that the RTOR components are a presubmission. When the last component is 
submitted, the applicant should identify that the application is complete. An updated Reviewers 
Guide should be submitted with each submission.15 
 
Where an application fee is required for the NDA or BLA under PDUFA, the fee must be 
submitted when the first component of RTOR is submitted to the marketing application.16  
 
15 See the technical specifications document: eCTD Technical Conformance Guide (November 2022). 
 
16 Sec. 736(a)(1), 736(e) of the Federal Food, Drug, and Cosmetic Act. 
6