By Jason Birri and Chris Kelly, Halloran Consulting Group
Seeking early guidance from regulators can be invaluable when navigating preliminary product development strategies. The need for feedback increases significantly when working with cell and gene therapy products (CT/GT). These therapies, once considered a kind of “wild-west,” are becoming more widely accepted. Still, the task of seeking approval from the FDA can be extremely challenging. It’s become vital to get your relationship with the FDA off to a solid start from day one.
The Pre-IND meeting offers sponsors an early opportunity to connect with the FDA, an important step to de-risk product development strategies and establish a productive collaborative relationship before initiating clinical studies. While sponsors commonly utilize Pre-IND meetings to solicit feedback on adequacy of preclinical studies and clinical design, sponsors of CT/GT products should consider directing certain Pre-IND discussions toward topics specific to Chemistry, Manufacturing, and Controls (“CMC”).
The FDA recognizes that CMC-specific discussions, during Pre-IND meetings, are typically unnecessary when projects are “straightforward.” However, unlike more traditional products, CT/GT are anything but straightforward. This novelty can create unique manufacturing roadblocks that impede the path to clinical development. To make matters even more challenging — CT/GT sponsors must grapple with the unending race between advancing technologies and the legislation that regulates them, as it’s nearly impossible for biopharmaceutical regulations to keep pace. Consequently, Pre-IND meetings are an opportune time for CT/GT sponsors to align with FDA on CMC strategies that will allow for product development while maintaining regulatory compliance.
The following examples highlight CMC-specific topics that sponsors should address during Pre-IND discussions for CT/GT products.
1. Selection Of Raw Materials
A key challenge for any developmental CT/GT product is the selection of appropriate quality raw materials. CT/GT products are extremely sensitive to slight changes in raw material quality which means that settling on research grade materials early in the process may pose significant challenges during later phase development. In addition, CT/GT manufacturing processes are sometimes reliant on animal- or human-derived raw materials. Ideally, process(es) should be optimized to exclude these materials in later phases, but barring that, sponsors should ensure that these materials are high-grade, suitably compliant and provided with the necessary supportive regulatory documentation. Consider discussing your approach to raw material selection with the FDA. Early engagement on this topic may reduce the need for significant process changes late in the game.
2. Adaptive Approaches To Manufacturing
As CT/GT research and development expands so does the diversity of product candidates entering clinical study. Correspondingly, sponsors are facing unique and previously unseen manufacturing challenges. For example, terminal sterile filtration — an essential component of the purification process for therapeutic proteins — can be nearly impossible to implement for certain viral vector-based gene therapies due to sensitivity and/or size of the virion. Similar issues are commonly encountered during development of sterilization processes for cell therapies. When facing of these types of challenges, consider alternative approaches using science- and risk-based justifications for the proposed control strategy in the absence of traditional practices. Early alignment between sponsors and the Agency can pave the way for manufacturing plans that are both technically viable and suitable to ensure phase-appropriate compliance.
3. Establishing Acceptance Criteria
A fundamental understanding of the product’s mechanism of action (MoA) is critical to appropriately identify and establish the critical quality attributes and critical process parameters. While that’s easier said than done for some CT/GT products, it’s important to gain FDA’s input on analytical methodology early in development. Ask yourself: are the proposed methodologies sufficient for the stage of development that you are in? Can surrogate assays be utilized to provide additional insight if you aren’t entirely sure of the MoA? Could the FDA recommend any additional attributes that should be evaluated and controlled? The FDA is gaining significant product-specific experience with the continued rise in CT/GT applications. They may be able to help steer you in the right direction to support specification development, based on their internal learnings from historical reviews.
4. Where The Guidance Doesn’t Fit
In several areas of CT/GT development the current guidance might not fit due to the nature of the product. There may not be enough final product to allow for retain sampling or full stability testing, too short of a shelf life to allow for traditional sterility testing, or analytical methodology that simply doesn’t work with the product type. It can be a real challenge to follow some of the most basic requirements laid out by developmental guidance documents. Discuss these areas with FDA and provide some alternative solutions or controls to these issues. Ask FDA if these approaches will be suitable throughout the development of your program. It’s important to show FDA that you are acknowledging gaps that might exist and that you are trying to address them early. They understand the challenges that many CT/GT products experience and may provide some important guidance on your approach(es) and recommendations on the corresponding control strategy.
For first-time sponsors, the prospect of a formal meeting with FDA can be more daunting than a blind date, but with ample preparation and the proper tools, it's more than possible to nail the first impression. Despite the natural trepidation, all sponsors should exercise the opportunities to engage in early discussions with the FDA, as an important first step in establishing a strong working relationship and familiarizing the review division with the program. Recent FDA announcements highlight the Agency’s perspective on the critical nature of these early communications via the implementation of the Initial Targeted Engagement for Regulatory Advice on CBER ProducTs (INTERACT).
Although, the Pre-IND meeting has long been the gold standard for seeking preliminary feedback, sometimes a single interaction simply isn’t enough for complex programs. Therefore, in an effort to provide additional touch points during early development, INTERACT has been established as a new CBER initiative that will afford sponsors increased opportunity to connect with FDA staff, further upstream in the development process prior to a Pre-IND interface. In addition to streamlining development plans and vetting clinical considerations, the doubling of face-time with FDA also allows for expanded discussion pertaining to CMC-specific strategies.
The unique CMC challenges faced by CT/GT sponsors are not insurmountable, but they can significantly complicate the path to clinical study. Moreover, unlike traditional small molecule pharmaceuticals and well-characterized proteins, manufacturing processes for many CT/GT products must consider commercial scalability and viability at a very early stage. These challenges underscore the importance of CMC-focused communications with the FDA early and often. By maximizing INTERACT and Pre-IND engagements, sponsors can work collaboratively with the Agency to de-risk complex CMC-specific road-blocks on the road toward bringing these pioneering medicines from concept to patients
About The Authors:
Jason Birri is a senior consultant for Halloran Consulting Group. He has more than 12 years of experience in biopharmaceutical drug development including roles in regulatory affairs, analytical development, and quality control. In his current role, Birri supports CMC (chemistry, manufacturing, and controls) aspects of product development and registration spanning a broad diversity of product classifications (e.g., CT/GT, biologics, and small-molecule products). He has navigated numerous global investigational drug filings and initial marketing applications in the U.S. and EU. In addition, Birri has a strong background in health authority interactions having led several successful CMC-specific meetings with various regulatory agencies. He holds a M.S. in regulatory affairs for drugs, biologics, and medical devices from Northeastern University, and earned a B.A. in biology with a minor in psychology from the University of Rhode Island.
Chris Kelly is a senior consultant for Halloran Consulting Group. He brings more than 18 years of experience in the biotech industry with 13 years of experience in regulatory affairs, focused on chemistry, manufacturing, and controls (CMC). Kelly has extensive experience in both investigational and marketed biologics including protein therapeutics, monoclonal antibodies, and cellular therapies. He has worked on several clinical trial and marketing applications for U.S., EU, Japan, and other global regions and leads regulatory strategy and execution. Kelly holds an M.S. in regulatory affairs for drugs, biologics, and medical devices from Northeastern University, and he earned a B.A. from Wheaton College with a major in biology.