Introduced in 1992 as a response to the HIV/AIDS crisis[i], the FDA’s accelerated approval pathway has been instrumental in providing oncology patients with earlier access to potentially life-changing treatments. The mechanism has played a key role in encouraging investment in oncology drug development by providing a faster route for bringing new treatments to market, and certain trends and developments highlight its continued evolution.
Historically, therapies that receive accelerated approval have fewer, smaller, or shorter clinical trials – often with a single arm. Study design requirements are now shifting, with growing preference for randomised controlled trials (RCTs). In addition, while sponsors have predominantly leveraged the accelerated approval pathway in late lines of treatment, the Oncology Center of Excellence’s introduction of Project FrontRunner seeks to change this by encouraging sponsors to develop and seek accelerated approval of metastatic disease therapies in earlier clinical settings.
The accelerated approval pathway has paved the way for additional FDA programs supporting expedited development and review of drugs addressing unmet medical needs. Each program comes with its own features, from frequent regulatory interactions to rolling review, intensive guidance on efficient drug development, and shorter review timelines for NDA/BLAs. The specific mechanisms include:
- Fast track designation, which can be applied for based on non-clinical or clinical data demonstrating the drug has potential to address an unmet medical need;
- Breakthrough therapy designation, for which preliminary clinical evidence must be provided indicating that the drug may demonstrate substantial improvement on a clinically significant endpoint over available therapies;
- Priority review designation for drugs that, if approved, would provide a significant improvement in safety or effectiveness.
Meeting the requirements for accelerated approval
Drugs eligible for accelerated approval must be intended to treat a serious condition and provide a meaningful advantage over existing, traditionally approved therapies available in the US for that same indication.
The FDA’s decision to grant accelerated approval is based on the drug’s ability to demonstrate an effect on an intermediate endpoint – one that can be measured earlier than overall survival (OS) and that is reasonably likely to predict an effect on Irreversible Morbidity or Mortality. A type of intermediate endpoint known as surrogate endpoints could include specific laboratory measurements such as biomarkers, radiographic imaging, physical signs, or other measure(s) that could predict clinical benefit but not itself be considered a direct measure of it.
Examples include Overall Response Rate (ORR) and Duration of Response (DOR). ORR is acceptable for single-arm trial designs but must exceed a historical benchmark and be durable, which is measured by DOR. Progression-Free Survival (PFS) may be accepted based on interim analysis in a RCT where follow-up for OS is expected to take significantly longer.
The FDA also requires that a confirmatory study be “underway” at the time of accelerated approval, with new guidance published in January 2025 providing detailed conditions regarding patient recruitment status and data collection and analysis timelines. This post-marketing trial is instrumental in confirming the anticipated clinical benefit. Should the sponsor fail to conduct this trial with due diligence, or should the study fail to produce the necessary confirmation, FDA approval may be withdrawn. Since 2015, withdrawals have been seen for 21 cancer therapies with accelerated approvals, while 51 oncology drugs originally authorised via this pathway have now gained full approval.[ii]
With the FDA recently highlighting the limitations of single-arm trials, utilising the RCT approach can help sponsors lower the withdrawal risk. This could comprise two RCTs (one trial to support accelerated approval and a confirmatory trial to support full approval) or a single RCT with longer-term follow-up supporting both accelerated and full approval.
However, when seeking accelerated approval of a rare oncological disease asset, sponsors may consider an innovative single-arm trial design with a historical comparator arm derived from real-world evidence (RWE). Incorporating this into the design allows for a comparative evaluation of the new treatment against previously collected data from similar patient populations, providing valuable context and supporting the decision-making process for expedited approval.
For drugs that received accelerated approval based on a single-arm trial, a confirmatory post-marketing RCT evaluating PFS and/or OS will be requested to close the evidentiary gap. The FDA highly recommends early regulatory interactions for discussing trial designs of both the study intended to support accelerated approval and the one supporting full approval.
Accelerated approval Q&A with Fortrea: What drug developers need to know about aligning with best practice
What timelines do you recommend for regulatory interactions regarding an accelerated approval, and what points should be prepared and discussed as part of these meetings?
It is essential to start with the end in mind (i.e., registration and approval timelines) and map this out into a plan that begins with defining patient population, labelling strategy, and confirmatory trial design. This plan can then be integrated with timelines for regulatory interactions across each study phase.
When predicting an accelerated approval date relative to the status of an ongoing confirmatory trial, key considerations include the target patient population, potential changes in the standard of care (SOC), and data requirements from regulators (i.e. rolling review or full clinical study report versus tables, listings and figures only).
The desired labelling and product claims should be planned out prior to any discussions with the FDA. During initial meetings, aspects such as the desired patient population and required data to meet the labelling requirements should be discussed and agreed. Sponsors should ask the FDA what exposure-response analysis will be required in the clinical study report (CSR), i.e., correlation of pharmacokinetics with adverse events, pharmacodynamics, and tumour shrinkage.
Finally, in the case of a precision oncology asset, early alignment on the co-development of an in-vitro companion diagnostic should be considered to avoid delays.
What fundamental considerations should be evaluated during the creation of the clinical development plan?
In line with the regulatory requirements of Project Optimus, it is important to establish an optimal dose as early as possible. Sponsors should also consider other randomised dose groups and share these in support of their applications.
If a drug shows promising activity in multiple tumour types, the sponsor must decide either to pursue the most promising single tumour type (e.g., based on high unmet need, strong efficacy signals, fast enrolment) or to pursue a tumour-agnostic path in case there is a common biomarker across tumour types (e.g., MSI-H, NTRK fusions) and consistency in response.
What aspects of trial design should sponsors consider in advance of and during discussions with regulators?
Sponsors should consider whether the trial design should be seamless in nature or segmented with clear stopping criteria. Seamless designs are optimal for efficiency but require a clear understanding of the potential changes to limit the number and impact of protocol amendments. Alternatively, although less time-efficient, sequential programs allow sponsors greater control over study changes.
Endpoint selection is the other key consideration with accelerated approval applications. Clinical endpoints for accelerated approval need to be linked to the asset’s clinical benefit. In today’s solid tumour space, these are typically focused on ORR and DOR. If PFS or OS are used, PFS must be assessed against a control arm with the results guided by the size/significance of the effect, while OS can be referenced against the SOC for the specific indication.
Sponsors can also consider the option to augment or even replace the control arm with RWE (i.e. a synthetic arm) in situations where randomising to a control arm is especially challenging, as with rare cancers.
What are the main operational considerations when conducting studies intended to support an accelerated approval?
The first consideration for both the study supporting accelerated approval and full approval is typically the timelines for milestone delivery, such as study start-up, first patient in, last patient in, and primary endpoint data availability. Sponsors will also need to assess the requirements for imaging scans collection and blinded independent central review. Best practice is to ensure ongoing scan collection and central archiving in case further regulatory review is required.
It is also important to consider pharmacokinetic (PK) analysis requirements, and this will depend on the asset type. In addition, the criteria or justification for dose expansion cohorts based on safety and early efficacy indicators defined in the protocol should be discussed with regulators. Sponsors need to be ready to provide this data to the FDA in order to support an expansion in pursuit of accelerated approval.
Finally, sponsors should look to put together a communication plan with investigators recruiting patients into both studies to explain the overall strategy. This can include any specific demands for data analysis, key deliverable timelines, and updates on readouts and regulatory decisions.
Why should a sponsor consider Fortrea for supporting in this space?
Fortrea is a leading global provider of clinical development and patient access solutions to the life sciences industry and a key partner to emerging and large biopharmaceutical, medical device and diagnostic companies with over 30 years of experience in the space. Indeed, over 85% of our client base are biotech customers, who expect an end-to-end clinical service in which they can maximise the value of the investment. Fortrea leads on an average of 40-50 agency meetings globally each year, supporting 10-12 clinical development plans annually. Additionally, we have conducted and are actively managing 225+ Phase II trials, many designed to support accelerated approvals, along with 230+ Phase III registrational or confirmatory oncology trials.
Our dedicated oncology team has over 2,000 staff globally, including over 50 physicians with oncology expertise supported by operationally focused clinical, project management and strategic personnel selected for their depth and breadth of oncology operational expertise when it comes to anticipating risks and delivering the right solution the first time.
[i] https://www.hematologyandoncology.net/archives/july-2022/lessons-learned-from-the-accelerated-approval-of-cancer-drugs/
[ii] https://www.fda.gov/drugs/resources-information-approved-drugs/verified-clinical-benefit-cancer-accelerated-approvals
