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- Kisqali Approval Press Release
- SBIA Webinar: Writing the “Indications and Usage” Section of Labeling: FDA’s New Draft Guidance - September 27 @ 1:30 EDT
- Electronic Drug Registration and Listing Using CDER Direct Conference - October 2, 2018
- FDA & MHRA Good Clinical Practice Workshop: Data Integrity in Global Clinical Trials – Are We There Yet? - October 23-24, 2018
- Clinical Investigator Training Course - November 13-15, 2018
The FDA has started using real-time review of drug applications to evaluate clinical data as soon as the trial results become available. This means that the FDA can approve a new indication soon after an applicant files a marketing application. Currently, this approach is only being implemented by FDA’s Oncology Center of Excellence (OCE) through two pilot programs for supplemental applications to already-approved cancer drugs. However, this could later expand to new drugs and biologics.
FDA was able to start analyzing data for the recently approved Kisqali (ribociclib) application before the it was submitted, and was able to help guide the applicant’s analysis of the top-line data to tease out the most relevant information. Originally approved in 2017, Kisqali received approval for additional indications for breast cancer under the pilot less than one month after the June 28th, 2018 submission date, and several months ahead of the goal date.
The standard review time goal for drug applications is six or ten months, as outlined by the Prescription Drug User Fee act (PDUFA) VI Reauthorization Letter. In contrast, the two pilot programs aim to approve supplements much sooner. The goal is to increase the efficiency of the development and review of cancer drugs and improve FDA’s rigorous standard for evaluating efficacy and safety by enhancing the process for evaluating the data submitted to us.
What does this mean? It’s a win-win situation across the board for industry, FDA, health care providers and patients. FDA will have more time to engage with applicants and focus on the key aspects of drug reviews, and health care providers and patients will benefit from the availability of drug products.
Real-Time Oncology Review (RTOR) Pilot Program: The first pilot program being utilized by FDA, called the RTOR, focuses on early submission of data that are the most relevant to assessing the product’s safety and effectiveness. RTOR allows the FDA to review much of the data earlier, after the clinical trial results become available and the database is locked, before the information is formally submitted to the FDA.
Eligibility criteria: The following criteria are used for a supplemental new drug application to be selected for RTOR:
- Drugs likely to demonstrate substantial improvements over available therapy, which may include drugs previously granted Breakthrough Therapy Designation for the same or other indications. Drugs meeting other criteria for other expedited programs (e.g. fast track, priority review) may also be considered.
- Straight forward study designs, as determined by the review division and the OCE. Studies conducted exclusively outside the U.S. and adjuvant, neoadjuvant, and prevention studies will be excluded.
- Endpoints that can be easily interpreted (for example, overall survival in a randomized trial).·
- Supplements with chemistry, manufacturing and control formulation changes and supplements with pharmacology/ toxicology data will be excluded.
- Submissions with greater complexity, including those with companion diagnostics, may also be excluded for the purposes of the pilot program.
Process: At the time of top-line results of a pivotal trial, if the above eligibility criteria are met, an applicant can apply for the RTOR pilot by notifying the appropriate FDA review division Regulatory Project Manager. The review division and OCE management will jointly decide whether the application can be selected for the RTOR pilot program.
If FDA determines RTOR is an appropriate review pathway, the applicant can start sending pre-submission data to the Agency under the original new drug application (NDA) or biologics license application (BLA), 2-4 weeks after all patient data has been entered and locked in the database and the applicant is ready to request FDA approval. This package should include key raw and derived datasets, including safety/efficacy tables and figures, study protocol and amendments, and a draft of the package insert. The applicant should also submit key results, analysis, and datasets for other disciplines, if applicable.
The FDA will start evaluating the pre-submitted data for sufficiency and integrity, providing an opportunity to address data quality and potential review issues. The FDA can then provide early feedback regarding the most effective way to analyze data to properly address key regulatory questions. By the time the applicant submits the application to the FDA, the review team will already have completed the analysis and be familiar with the data, and can conduct a more efficient, timely, and thorough review. Early engagement may improve the quality of the NDA/BLA submission and FDA’s evaluation of the application.
Assessment Aid Pilot Project: The second pilot is a new Assessment Aid, a structured template based on the FDA Multidisciplinary Review template that the applicant uses to organize its submission into a structured format to facilitate FDA’s review of the NDA/BLA, including supplements. The Assessment Aid creates a more efficient and streamlined review process and reduces the administrative burden on FDA reviewers by permitting them to focus on key results and perform critical analyses that may have been omitted by the applicant. In turn, it leads to a more dynamic review process where key regulatory questions can be answered more thoroughly and effectively.
Process: The Assessment Aid template is sent to the applicant during the Investigational New Drug (IND) stage. An applicant can communicate interest in participating in this pilot program to CDER’s Office of Hematology and Oncology Products by sending a notification of interest to the FDA Regulatory Project Manager prior to application submission or at the pre-NDA/BLA meeting.
The applicant will add their position once top-line data are received in anticipation of an original or supplemental NDA/BLA submission. If participating in the RTOR program, the applicant may submit the Assessment Aid before or around the time of NDA/BLA submission. The applicant portion should be concise and only include critical information. The FDA review team, after conducting their scientific evaluation, will add their assessment in response to the applicant’s position, using this same template. FDA’s assessment will focus on whether or not FDA agrees with the applicant’s position, and any additional findings and analyses. By using a structured template, the FDA can layer its assessment into the same file submitted by the sponsor, allowing this annotated application to serve as the document that contains the FDA review.
Those applicants who do not wish to participate in the Assessment Aid pilot will follow the usual submission process with no impact on review timelines or benefit-risk decisions. Note that there is no definite timeline for the pilot programs. An analysis will be conducted after each CDER Office of Hematology and Oncology Review Division has completed the pilot. In addition, there are no user fees since the pilot is for supplemental applications. If the pilot is expanded to original drugs and biologics, the FDA will determine when to assess the PDUFA fees.
As FDA and applicants embark on this exciting new venture, we hope to improve regulatory review efficiency and further solidify our review standards, while reducing administrative burdens that can add to the time and cost of the review process. Our goal, as always, is to ensure that safe, effective and quality treatment options are available to patients as early as possible.
Renu Lal, Pharm.D.
CDER Small Business and Industry Assistance
This communication is consistent with 21CFR10.85(k) and constitutes an informal communication that represents our best judgment at this time but does not constitute an advisory opinion, does not necessarily represent the formal position of the FDA, and does not bind or otherwise obligate or commit the agency to the views expressed.