TrialSite News recently reported on the approval of Novartis’ alpelisib for treatment of postmenopausal women, and men with positive HR-positive, HER2-negative, PIK3CA-mutated, advanced metastatic breast cancer following progression on or after an endocrine-based regimen. The FDA approved this targeted therapy via its Real-Time Oncology Review pilot program. (RTOR) TrialSite News sought out to better understand this program and provide a summary to the readers.
What is the FDA Real-Time Oncology Review Pilot Program?
The agency sought out a more streamlined and efficient way to review applications. The goal is efficiency of the development and review of cancer drugs. They also seek to improve the FDA’s rigorous standard for evaluating efficacy and safety by enhancing the process for evaluating the incoming data as part of the submission package.
The FDA seeks to achieve “win-win” scenarios. By securing more quality time to engage with applicants, they can focus on key aspects of drug reviews. The program’s premise is patients and healthcare providers will benefit from greater availability of drug products.
The FDA’s first pilot program RTOR, focuses on early submission of data that are the most relevant to assessing the product’s safety and effectiveness. The FDA sought to have the flexibility to review important segments of submission data earlier in the process—after the clinical trial results are available and the clinical trial database is locked—but before the information is formally submitted to the FDA.
What is the Eligibility Criteria?
The FDA has published criteria utilized for supplemental new drug applications to be selected for RTOR:
- Drugs that are 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 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 (e.g. 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.
What is the Process?
An applicant can apply for the RTOR pilot by notifying the appropriate FDA review division Regulatory Project Manager if at the time of top-line results of a pivotal trial the above eligibility requirements are met. The FDA review division and OCE management will jointly decide whether the application can be selected for the RTOR pilot program.
If the 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.
- The package should include:
o Key raw and derived datasets-including:
- Safety/efficacy table sand figures
- Study protocol and amendments
- Draft of the package insert
o Applicant should also submit key results, analysis, and datasets for other disciplines if applicable
- The FDA thereafter starts its RTOR evaluation by undertaking the following:
o Evaluating the pre-submitted data for sufficiency and integrity
o Provide an opportunity to address data quality and potential review issues
o Provide early feedback regarding the most effective way to analyze data to properly address key regulatory questions
- Once the applicant submits the application package to the FDA, the Agency’s review team will have already completed the analysis and be familiar with the data, and consequently, the Agency will be in a better position to conduct a more efficient, timely and thorough review.
- An key assumption here: early engagement may improve the quality of the NDA/BLA submission and FDA’s evaluation of the application
The second pilot is a new Assessment Aid.
What is the Assessment Aid?
The FDA’s Oncology Center of Excellence developed the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment of an NDA/BLA application including supplements.
Based on a FDA Multidisciplinary Review template, the sections are divided into two parts for most parts of the template. They include 1) The Applicant’s Position and 2) The FDA’s Assessment
The main objectives of the Assessment Aid include:
- Focus the FDA on critical thinking (assessment)
- Increase review efficiency and consistency, and decrease review time spent on administrative tasks such as formatting
The Assessment Aid template is sent to the applicant during the IND stage. An applicant can communicate interest in participating in the 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 the application submission or at the pre-NDA/BLA meeting
- The applicant adds 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, post scientific evaluation, will add their assessment in response to the applicant’s position, using the same template.
- The FDA’s assessment focuses on whether or not FDA agrees with the applicant’s position, and any additional findings and analyses.
- The structured template enables the FDA to 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.
- If applicants do not want to participate in the Assessment Aid pilot, they must follow the usual submission process with no impact on review timelines or benefit-risk decisions.
There is no definite timeline commitment for the pilot programs. An FDA analysis is conducted after each CDER Office of Hematology and Oncology Review Division has completed the pilot. 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.
The FDA hopes to improve regulatory review efficiency while simultaneously solidify and continuously improve review standards. The hope is that the Agency reduces administrative burden on sponsors that can add time and cost to the formal FDA review process. As concluded by Renu Lal, Pharm.D., CDER Small Business and Industry Assistance, “their goal, as always, is to ensure that safe, effective and quality treatment options are available to patients as early as possible.”