FDA issues guidance and recommendations for New Drug Applications (NDA) and Biologic Laboratory Applications (BLA) which implicate oncology therapies and warrant Real-time Oncology Review (RTOR). On July 25, 2022, the FDA, by and through the Oncology Center for Excellent (OCE), the Center for Biologics Evaluation and Research (CBER) and Center for Drug Evaluation and Research (CDER), issued recommendations for New Drug Applications (NDA) and Biologic Laboratory Applications (BLA) which may be eligible for Real-Time Oncology Review (RTOR). The RTOR program was established in 2018 "to facilitate earlier submission of top-line results and datasets, after database lock, to support an earlier start to the FDA application review" process. While the program was initially limited to supplemental oncology drug applications, eventually NDAs for "new molecular entities" and "original oncology BLAs" were also eligible for RTOR review.

The RTOR program facilitates the early submission of "critical efficacy and safety data" to initiate FDA's evaluation" of an application at separate times for different components of clinical module submissions. In essence, the RTOR allows the FDA to streamline the review process, provide early feedback to applications and to encourage early engagement with the FDA reviewer(s). Notably, "top-line" efficacy and safety results from pivotal clinical trials" are required for RTOR submissions. Eligible applications must demonstrate:

  1. Drug is likely to demonstrate substantial improvement over available therapy or to qualify for FDA's Expedited Programs
  2. Straightforward study designs as determined by the review division and the OCE
  3. Easily interpreted clinical trial endpoints (e.g., overall survival, response rates), as determined by the review division and OCE

The FDA also provided specific guidance for applicants in how to initiate NDA/BLA submissions into the RTOR program. For instance, it recommended applying for RTOR review once "top-line results of a pivotal trial(s) are available, and the database has been locked" by email submission to the applicant's assigned Regulatory Project Manager and to the Investigational New Drug Application (IND). That requires "should include their (the applicant's) top-line results and a written justification explaining how their application demonstrates that it is appropriate for RTOR" submissions. Generally, the FDA will advise if the applicant meets RTOR eligibility within twenty (20) business days. If the applicant does not meet the RTOR criteria, the application should follow the traditional submissions protocols. Once the applicant and the FDA agree upon potential RTOR review and an agreeable timeline, the following items should be submitted by the applicant into no more than three (3) partial submissions, followed by a "final submission":

  1. Top-line efficacy/safety tables/figures
  2. Complete Study Data Tabulation Model (SDTM)
  3. Dataset package
  4. Complete Analysis Data Model (ADaM) datasets for key efficacy and safety tables/figures for pivotal study (see OOD data specifications9 for requested format of safety datasets)
  5. The protocol and amendments (a list of major changes for each amendment), Statistical Analysis Plan (SAP), and Data Monitoring Committee (DMC) charter and DMC minutes
  6. Statistical (e.g., SAS) programs Proposed labeling
  7. Summary of data and rationale supporting dose and dosing regimen selection (including key population pharmacokinetics (PK), physiologically based (PB)/PK and exposure-response reports, analyses programs, and datasets)
  8. Summary of clinical pharmacology studies and datasets supporting the conclusions
  9. Key results, analysis, and datasets for other disciplines (e.g., clinical pharmacology), if applicable
  10. Final study reports of all supportive studies, including pharmacology and toxicology studies
  11. Case report forms (CRFs) as required by applicable regulations
  12. All Chemistry, Manufacturing, and Controls (CMC) information, if appropriate, including list of all manufacturing, testing and critical intermediate facilities with addresses and FDA Establishment Identifier (FEI) numbers other than stability data for registration batches (if not available) for drug substance(s) and drug product

While entry into the RTOR program does not guarantee approval of an NDA or BLA, or implicate the Fast Track Designation, Breakthrough Therapy Designation, or Priority review Designation, submission to the program has significant benefits to applicants. Arguably, the biggest benefit is the potential for "early engagement" with the FDA reviewer(s) regarding NDA or BLA components and in identifying issues with submissions early on.

Source: https://www.regulations.gov/docket/FDA-2022-D-0823

Ismail is a multi-jurisdictional practitioner with substantial experience in business and intellectual property transactions and disputes. Ismail has handled disputes all over the world and throughout the United States on behalf of Fortune 500 companies and mid-sized privately held companies in diverse fields such as healthcare, biologics, biotechnology, financial services, payment processing and hospitality.

TALG's record of success includes consummating over $50 Billion worth of transactions over the course of 17 years. In the Courtroom, we've successfully obtained substantial verdicts in favor of our clients. On the defense side, we've saved our clients over $100 Million through a hybrid approach of aggressive advocacy while utilizing cutting-edge technologies.

To read more about TALG and the industries we serve, click here: https://talglaw.com/

Originally Published by TALG Law

The content of this article is intended to provide a general guide to the subject matter. Specialist advice should be sought about your specific circumstances.