Regulatory CMC Experts Navigate Accelerated Approval Timelines

Picture this: a pharmaceutical company just received an accelerated approval designation by the FDA for their lead candidate, though exciting, the expedited timelines and deliverables felt like their team was reaching for the stars. Meeting expedited timelines and scenario planning became the main focus for this team, and they began evaluating the demands, risks, and benefits of the designation, and asked themselves ‘can we really pull this off?’

Regulatory Chemistry, Manufacturing, and Controls (CMC) experts on the team reiterated that the manufacturing and characterization requirements to ensure product safety and quality are not relaxed, but the timing is adjusted. Even understanding this compressed timeline before they applied for accelerated approval, the company is still left facing manufacturing deliverable concerns and in retrospect, wished they had established more proactive planning before submitting their application.

Below you’ll find ideas on how to bring a Regulatory CMC ‘checks and balances’ perspective early on around navigating expedited timelines for accelerated approval designations before the application is submitted.

Accelerated Approvals: Saves Time, but Requirements Remain

An Accelerated Approval allows product developers to save significant time because the FDA may consider the product reasonably likely to predict a real clinical benefit based on a surrogate endpoint. Successful utilization of an expedited program can reduce development time by more than two years when compared to traditional drug development timelines, sometimes reaching 15+ years. Such a designation, however, demands a diligent development plan with advanced scenario planning before the accelerated approval application is submitted. In addition to robust timelines, accelerated approvals also allow more opportunities for sponsors to engage with the FDA and become a partner in advancing an unmet medical need.

But this time savings can introduce major challenges for regulatory CMC aspects of product development since expedited development does not lessen regulatory safety requirements.

Navigating the Risks of an Accelerated Approval Designation

We cannot overemphasize the value of upfront planning. Product developers should discuss the possibility of accelerated approval with the review division of the FDA during development, including the use of the planned endpoint that is reasonably likely to predict the intended benefit of the drug as a basis for approval. Having these upfront planning discussions will help ease the burden of ‘can we pull this off’ after receiving the designation and move the team into a more proactive mindset.

Additionally, the developers should also discuss their confirmatory trials with the FDA and there should be an agreement with the FDA on the design and conduct to support the confirmation of the clinical benefit. Typically, the confirmatory trial should already be underway at the time of the application for accelerated approval.

Balancing development activities once an accelerated approval has been granted can be a tricky game, often resulting in a lot of risk management. As companies identify with the above scenario, it’s important to pause and create a risk assessment and strategy well in advance to meet the expedited timeline demands.

Risks and opportunities, but certainly not limited to:

• Expedited manufacturing process
  • Manufacturing planning should be done well in advance of the application and should be a priority from the beginning. In fact, these internal discussions should occur throughout development since the product is being updated throughout the lifecycle of the proposed product. Once the New Drug Application (NDA) or Biologics Licensing Application (BLA) is submitted, there is limited manufacturing time from the approval to the time of commercial product launch, which puts pressure on the team to select a manufacturer and outline the product manufacturing plan.
  • Issues relating to scale-up for commercialization and formulation changes required for commercial supply could arise. To quickly make an effective decision, map out must-have criteria during the bid defense meetings and select the manufacturer that aligns with the development goals and timeline. Ensure the manufacturers are also compliant and there is not a lengthy list of issues identified during previous inspections by either the sponsor or health authority.
• Changes to manufacturing sites
  • There may be changes to commercial manufacturing sites and their operations, so consider a commercial launch prior to scaling up product development and consider technology transfer to the final commercial facility to accelerate development. Changes to manufacturing sites are not unheard of and could be needed for a variety of reasons. Still, it’s important to plan how to incorporate these changes and demonstrate comparability along the way. With careful prospective planning, the launch can be performed from a clinical site on a smaller scale. In order for this to align, discussions with clinical team members should occur to determine sites as early as possible.
• Limited stability data
  • Stability data is the data collected on the product to understand its ability to retain its chemical, physical, microbiological, and biopharmaceutical properties within specified limits throughout its shelf life. Understand the risk of limited registration stability data at the time the NDA or BLA filing has been submitted.
  • Consider providing updated stability data within 30 days of the initial submission, and if agreed, submit less than 12 months of data at the time of submission. Remember, you have the opportunity to engage with the FDA more frequently (and earlier) with accelerated approvals so having stability discussions and agreements is the key to risk mitigation.
• Expedited method development
  • There is often a limited dataset available to establish commercial methods and specifications because the method development is quickly formulated to meet the demand. Focus on high-priority assays by engaging with FDA early, holding multiple touch points, and introducing key assays prior to registration stability studies. Use validated methods and testing facilities for commercial release and perform expanded robustness studies earlier in development to push the boundaries and maintain those validated methods.
  • Consider supply chain and shipping delays. While not ideal, scenario planning for such delays provides an understanding of the “what could be” timeline.
• Inevitable changes during the development process
  • Accelerated approvals lock in the “to-be-marketed” formulation as quickly as possible following the acceleration to secure agency buy-in, but this leaves little room for adapting to changes while still meeting the timelines. During these challenging times, be sure to properly document all changes and capture as much context as possible so that quality procedures and processes are woven through the development process every step of the way, so a successful audit or inspection isn’t jeopardized.
  • Alternatively, as some of the inevitable changes occur, it’s critical to demonstrate that the intended changes are not introducing anything new or increasing what’s already been shown to be safe. Tie your planned commercial batches back to your early development batches, especially your toxicology batch, to show the impurities remain within qualified safety limits. By doing so, you’re alleviating time-intensive (and expensive) additional studies, including nonclinical studies.
• Inspection readiness
  • Inspection readiness plans can be more reactive because of the accelerated timelines, so preparedness is essential, i.e., organizing documentation to be reviewed, identifying who will be available during the inspection and their responsibilities, etc. Remember, you’re also dealing with limited experience (with the process, product, and materials), so you’ll be figuring this out as you go. Planning and strategizing preparedness keeps you on track so you’re not putting out unnecessary fires. A helpful opportunity includes holding a mock inspection with experienced auditors.

Every product development path is unique and has its challenges, and when introducing potential new challenges such as expedited timelines, it’s absolutely essential to understand risks and mitigation strategies upfront so that when the FDA grants an accelerated approval designation, you’ll be able to move forward with a strategic plan and make minor adjustments along the way.

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To learn more about Halloran’s Regulatory CMC capabilities, please contact a member of our team to learn more about how we help companies like yours navigate accelerated development pathways.