As family members and caregivers, it is a fundamental human instinct to do everything possible for the cancer patients in our lives. These moments challenge and define us. We leave no stone unturned in providing comfort and seeking out the best care and, in doing so, exert what control we can over the unpredictability of illness. As drug development professionals we have a unique opportunity to extend this approach beyond our friends and families to the patients who enroll in the clinical trials we oversee. From a regulatory perspective, a key part of “leaving no stone unturned” is understanding the full scope of programs offered by the FDA to speed up the approval of cancer treatments. In this spirt, a review of these programs is provided below.
Core FDA Expedited Programs for Serious Conditions
Over the last 20 years, the FDA has released several guidances intended to speed up the development of treatments for serious conditions. Conceptually, it is useful to organize these in terms of programs that are applicable broadly to serious conditions and those specific to oncology. In the first category are those programs covered by the This guidance describes four expedited pathways, which we have covered in previous blogs (see MMS blog on “FDA Program Designations To Support Rare Disease Drug Development (mmsholdings.com)) and are described briefly below.
Fast Track
The Fast Track Designation helps facilitate the development and expedite the review of new drugs by granting sponsors:
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- More frequent meetings and written communication with the FDA
- Rolling Review
For oncology products a key decision point in applying for Fast Track designation is the ability to meet qualifying criteria for demonstration of potential to meet an unmet need. Typically, in oncology this would include strong nonclinical pharmacology data and/or preliminary clinical efficacy. Sponsors generally apply as soon as they are confident in their preliminary data.
Breakthrough
The Breakthrough Therapy designation is for new drugs that may demonstrate substantial improvement over existing therapy on one or more clinically significant endpoints, or on symptoms that are serious consequences of the disease, to provide sponsors with the following benefits:
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- More frequent meeting and written communication with the FDA
- Rolling Review
- Involvement of FDA senior managers
- Intensive guidance on an efficient drug development program
As is the case for Fast Track, ability to meet qualifying criteria typically determines when Sponsors file for Breakthrough Designation. Only here, the standard is preliminary clinical evidence that the drug may demonstrate substantial improvement over available therapies. Supporting this standard requires careful consideration, particularly where multiple available therapies exist.
Priority Review
Priority Review is used to evaluate drugs that potentially provide significant improvements in the safety or effectiveness of the treatment, diagnosis, or prevention of serious conditions over standard process, and offers the following benefit:
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- Shorter NDA/BLA review time by 4 months compared to standard review time
Priority review is a decision taken by the Agency following the filing of a supplemental or new NDA/BLA. While the Agency will make this decision for each application, sponsors may file a specific Priority Review Request supporting their position and should consider doing so if they have not previously provided a rationale for significant improvements in the safety or effectiveness of the treatment, diagnosis, or prevention of cancer, or if a previously submitted rationale has changed based on new data or subsequent approvals for the indication.
Accelerated Approval
The Accelerated Approval pathway to market authorization is based on two types of endpoints (either demonstrating an effect on a surrogate endpoint or an intermediate clinical endpoint that is reasonably likely to predict a drug’s clinical benefit or a clinical endpoint that is reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical benefits) to provide sponsors the following benefit:
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- Earlier approval based on surrogate or intermediate endpoints with full approval conditioned on confirmatory trials.
Key decision points for accelerated approval are complex and will be covered in detail in subsequent blogs. Justification of surrogate and intermediate endpoints along with plans for confirmatory post-marketing studies, are critical components
Oncology Specific Programs
In addition to the programs listed in the 2014 guidance, several additional programs exist specifically to speed up the development and approval timelines of oncology products. These include Project Orbis, the submission of Assessment Aids, and the use of the Real Time Oncology Review process.
Project Orbis
Project Orbis, initiated by the FDA Oncology Center of Excellence in May 2019, establishes a framework for the concurrent submission and review of oncology drugs among international regulatory partners. This collaboration aims to provide cancer patients with earlier access to treatments across different countries, potentially reducing delays in regulatory approvals.
The project leverages international pivotal clinical trials to assess the safety and efficacy of cancer drugs, fostering the establishment of uniform global treatment standards. By promoting simultaneous reviews and approvals, Project Orbis facilitates faster access to new therapies, thereby expanding the availability of innovative cancer treatments to a larger global market.
Collaboration among international regulators can lead to more rapid access to larger markets by streamlining the regulatory process across multiple countries. This means that once a drug is approved in one participating country, it can be more swiftly approved in others, reducing the time patients must wait for new treatments. The unified approach helps overcome regional regulatory barriers, allowing for a more efficient distribution of new oncology therapies worldwide.
When considering project Orbis, sponsors should bear in mind the general challenges inherent in multinational submissions from data and regulatory perspectives with specific emphasis on the impact of accelerated timelines on coordination of regulatory advice, gap analysis of submission requirements, and management of information requests.
Assessment Aid
Based on the FDA Multidisciplinary Review template, the assessment aid focuses on the FDA review on critical thinking (assessment) to increase review efficiency and consistency. It is a stand-alone document with a generic structure covering the application’s key points, which reduces ambiguity and allows the Agency to more effectively perform their analysis. A strong Assessment Aid serves not just as a summary of the NDA/BLA, but also as a statement of sponsor position, reducing ambiguity and allowing the FDA to more effectively perform their analysis. A key expected benefit of this approach is a reduction in information requests.
As the Assessment Aid is generally submitted with the NDA/BLA, a key decision point for sponsors is whether the extra effort to produce the document is worth the benefits that arise from a more focused FDA review. The answer to this question may lie in advanced preparation, particularly in the form of quality written summaries that can be extracted and adapted to produce an effective assessment aid
Real Time Oncology Review (RTOR)
The Oncology Center of Excellence (OCE) Real-time Oncology review (RTOR) Pilot program was initiated in February 2018, specifically for supplemental oncology new drug applications (NDA)s and biologic license applications (BLAs) of previously approved drug products. Beginning in December 2018, the RTOR program was extended to select original NDAs for new molecular entities (NMEs) submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), and original BLAs submitted under section 351(a) of the Public Health Service Act.
To streamline the review of promising new oncology treatments, the RTOR program allows sponsors an earlier application review start (as early as 2-4 weeks after the patient database lock of top line results from their pivotal trial). This early start provides an opportunity for early Agency engagement to proactively identify potential deficiencies and review top line clinical data. The FDA reports that those who used the RTOR process had a shorter median submission review to approval time of 3.3 months. Successful RTOR submissions are dependent on critical communication between the sponsor and the agency to agree on timelines for providing the requested data. It is important to remember that after the initial wave, RFIs from the FDA may continue to come in for each subsequent wave, necessitating simultaneous responses to initial RFIs and subsequent RTOR waves.
One of the main challenges of the RTOR process is the management of Information Requests from the FDA in parallel with ongoing submission planning. The frequent flow of Information Request involves tight turnaround times, typically within 24 to 48 hours. These requests may also impact future components of the rolling submission, which will need to incorporate the FDA’s feedback.
How MMS Can Help
Leveraging available expedited pathways for oncology products can be challenging for sponsors. At MMS, we are committed to advancing the fight against cancer through our expertise and experience in oncology. Our approach is centered on understanding the full scope of programs offered by the FDA to speed up the approval cancer therapies. ” We have the knowledge to successfully apply for expedited programs and the expertise to apply the benefits of these programs to your unique development plan. At MMS, we are passionate about leveraging these programs for maximum effect. From early discussions of study design though the final rolling review submission and beyond, let us help you shorten the path and leave no stone unturned. Subscribe now to the MMS newsletter and stay connected with the forefront of cancer research and treatment advancements.
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References
Authored by:
- Nancy Hsu, Regulatory Affairs Associate at MMS Holdings
- Ben Kaspar, Senior Director, Regulatory Affairs and Strategic Consulting
