Six Strategies for Accelerating Approval for Cell and Gene Therapies

After decades of slow and steady progress, cell and gene therapies are experiencing important breakthroughs, demonstrating the potential to slow disease progression, improve outcomes, and in some cases, potentially cure an array of illnesses. However, developers of these cutting-edge therapies are encountering new challenges as they navigate complex clinical and regulatory hurdles, particularly when they’re seeking accelerated approval.

Cardinal Health has a team of experts that understand the complexities and unique challenges that precision medicines face — and can offer a wide range of proven regulatory, commercial, logistical, financial, and access solutions for overcoming those obstacles. Cardinal Health Regulatory Sciences shares six proven strategies that can help cell and gene therapy sponsors reduce their risk of failure and expedite speed to market.

Content Summary

Start with a clear, highly collaborative framework for leadership and communication among disparate internal teams
Develop clear and consistent messaging early on and work cross-functionally to control, adapt and maintain message consistency throughout the product lifecycle
Demonstrate a clear understanding of your product
Develop — and continually adapt — realistic timelines and tools to keep development on track and aligned
Make the most out of each FDA interaction. Listen to and fully address their feedback.
Remember that accelerating development does not equal accelerated approval

Unlike traditional therapies that follow now tried-and-true processes for critical steps in the development process — like the clinical trial design — there is no “playbook” for cell and gene therapy development, due in large part to the unique, patient-specific nature of each dose and the potentially limited patient populations for each therapy. Adding to this complexity is the reality that the science behind cell and gene therapies is new to FDA reviewers, who are charged with asking new questions and determining which kinds of evidence are necessary to prove efficacy for each of these new therapies.

With traditional therapies that demand less complex manufacturing processes, upwards of 80% of the FDA’s review process focuses on questions related to clinical efficacy and safety, like: Does it work? Is it safe? What are the potential patient reactions? Just 20% of the FDA’s review process typically focuses on issues related to product manufacturing and delivery. For these products, the development of the proposed formulation evolves in parallel with clinical development.

This approach is flipped when it comes to cell and gene therapies, where manufacturing is more complex, and for autologous cell therapies, where “the product is the process,” because the degree of control a sponsor has over the manufacturing process directly correlates to how a sponsor controls the quality of each patient’s dose. For these innovative new therapies, quality aspects related to the manufacturing process drive the development program.

That’s why for cell and gene therapies, the FDA review focuses primarily on the therapy’s critical quality attributes and controlling these earlier in development, typically before clinical studies. Data on potency, product manufacture, how it’s delivered, and how it’s administered to the patient are required earlier in development.

Another key difference is that many cell and gene therapies are sponsored by small to medium-sized companies — many of whom have deep scientific and academic research expertise but may not have large teams of on-staff experts who have deep experience in understanding the complexities of working with regulatory health authorities, including the FDA.

Cardinal Health™ Regulatory Sciences has more than four decades of experience supporting pharmaceutical and biotech companies to get their products to market quickly. We’ve also supported a variety of emerging cell and gene therapies as they progress through the development pipeline.

Here, we share six proven strategies that can help cell and gene therapy sponsors reduce their risk of failure and expedite speed to market.

Start with a clear, highly collaborative framework for leadership and communication among disparate internal teams

In cell and gene therapy development, it can be quite common for multiple internal stakeholders — including clinical, nonclinical, quality, and marketing teams — to each drive their portion of the development process without communicating with each other. This lack of communication and alignment can cause costly missteps, rework, and delays. These challenges and delays can be avoided by taking the following steps — which may seem simple, but require continual focus and discipline to execute:

Establish a cross-discipline leadership team and frameworks to ensure this team communicates at key junctures throughout the development timeline. This structure can help ensure all stakeholders are aware of progress, findings, and challenges in the development process — so leaders can direct their teams to adapt and refine plans and timelines accordingly.
Create and secure buy-in for a comprehensive development plan that begins with the end in mind. Ensure your cross-discipline leadership team understands what information is needed for regulatory filings at each stage of development — and then work backward when creating your development plan. By knowing in advance what research and data you’ll need to get to the next step in development, you’ll be better able to prepare and align to important efficacy, safety and benefit-risk messages that need to be featured and reinforced through each phase. A fully fleshed-out plan also helps to ensure that all internal stakeholders are aligned on the project scope, that the necessary resources are allocated to complete each phase of the plan, and that all work is sequenced most optimally. This is especially critical for cell and gene therapies when multiple teams are working on their portions of the development plan simultaneously. The development plan should also clearly outline potential roadblocks that may slow the development process so that contingency plans can be created to address each one.
Regularly update and adapt your plan. Your development plan is a dynamic document that should continually evolve as you gain a better understanding of your product and interact with regulatory health authorities. Each cross-functional leader should play a role in tracking and documenting changes in the plan — and the reasons why each change is made — so all stakeholders have a clear line of sight updates and can develop contingency plans to address potential challenges.
Include external stakeholders — including contract manufacturing sites — in the review and maintenance of your plan. This is particularly important for cell and gene therapies that comprise multiple drug substances or critical starting materials that may each be manufactured at a different site because they must all come together in a coordinated manner to successfully manufacture the product. This step helps drive accountability and urgency, helps reduce the risk of incomplete or incorrect deliverables, and helps avoid unrealistic timelines and delays.

Develop clear and consistent messaging early on and work cross-functionally to control, adapt and maintain message consistency throughout the product lifecycle

One of the best and most important ways to maintain strategic alignment throughout the development process is to start by developing and agreeing on clear product messaging — defining efficacy, safety, and benefit-risk analyses — and then continually updating that messaging throughout the development process. This may seem like a simple task, but doing so within a cross-functional team requires forethought and planning.

Set and agree on critical terminology that will be used by all cross-discipline teams as they author their portion of reports and FDA filings. This step will ensure that each internal team is “writing in the same language” and helps ensure a consistent message is being shared with FDA reviewers.
Engage key opinion leaders (KOLs), patient advocacy groups, and other external messaging influencers early on in messaging discussions. This is a key consideration for developers of cell and gene therapies because KOLs and patient advocacy groups can play such an important role as champions for the approval of these advanced therapies, which often are developed for relatively small patient populations who are experiencing significant impairments. Their input can often have a significant impact not only on product messaging but also on clinical trial design and helping FDA reviewers understand the types of outcomes and benefits that are most valuable from the patient perspective. For example, reviewers may typically require clinical trials to prove a therapy’s efficacy by demonstrating improvement via specific clinical endpoints. However, that same therapy may be able to gain approval without those specific data, if its clinical trials can demonstrate that it positively impacts other outcomes that patients and their caregivers indicate would improve less scientifically measurable benefits, like improved quality of life. For clinical trials to be designed with meaningful endpoints in mind, this input needs to be gathered early from patients.
Assign specific team members responsible for developing both overarching and granular messaging to ensure consistency across all documents. Failure to assign specific team members to this task at the beginning of the development process can create costly delays later on, as the team works late in the game to identify and address messaging inconsistencies.

Did you know?

Maintaining active communication and interaction with external stakeholders, including standards organizations and policy-oriented groups like the Alliance for Regenerative Medicine, can help sponsors effectively integrate persuasive messaging in their Investigational New Drug (IND) submissions. Participation in these groups is often either free or on a sliding scale, so even small companies can still get involved.

Demonstrate a clear understanding of your product

There truly is no one-size-fits-all approach to developing and regulating complex cell and gene therapies. However, FDA reviewers expect all sponsors to demonstrate a very clear understanding of their product when submitting their IND. The better you understand how your product works, its critical quality characteristics, and its potential risk, the better you can design pivotal nonclinical safety and biodistribution studies, which track how and where compounds travel in an experimental animal or human subjects. This is the kind of information you need to access the kind of data needed to support the appropriate clinical trial design and starting dose, both of which are essential in supporting a favorable benefit-risk profile.

Follow a stepwise approach to nonclinical product investigations: This means starting with proof of concept (POC) studies to establish the feasibility of making and delivering the product; as well as the scientific rationale for the product in the proposed clinical indication. This may also include early studies to determine what happens to the product once it’s been delivered, for example, where the therapy travels once injected in the body. After or in parallel with POC studies, it’s important to assess the safety of the product so you can justify a starting dose and identify any special precautions that should be taken in the eventual clinical study, concerning eligibility criteria and monitoring.
Expect definitive IND-enabling studies to be hybrid: meaning that they will likely encompass study types in an animal model of disease with endpoints that satisfy multiple data requirements concerning assessing persistence, integration, on-target toxicities, and other variables.

If there’s no report, it didn’t happen

Health authorities can only make science-based decisions about risk-benefit based on the information you provide them. This makes it critical to record and file reports for each of your nonclinical studies. As far as the FDA is concerned, if there is no complete study report capturing the information from all preclinical studies used to support the safety and rationale of your proposed clinical trial, the research didn’t happen. These reports can include prospectively written protocols, detailed descriptions of study design, individual results for animal studies, and your analysis and interpretation of the data.

Develop — and continually adapt — realistic timelines and tools to keep development on track and aligned

Sponsors of cell and gene therapies often feel a sense of urgency to work hastily toward regulatory submission; this bias toward expediency can sometimes be amplified when key team members hail from academic backgrounds and are unfamiliar with the added level of scrutiny with which FDA reviews commercial IND applications vs. research-only IND applications. However, a sponsor’s ability to set and adhere to realistic development timelines will play a critical role in accelerating the approval process — and cannot be rushed.

Ensure your timelines are data-driven. Use gap analyses of early data to define what data you’ll need at each step in the development program. One of the best tools for assessing gaps, tracking progress, and planning for the future is to follow the eCTD table of contents and create an IND submission map. The eCTD structure forces each stakeholder in the development process to consider each discipline in a granular way. It is equally important to take into consideration how outside events, like pending regulations or emerging guidance, might impact your timeline.
Establish good communication among the sponsor, external stakeholders, and the FDA to ensure your timelines are realistic. Setting timelines in a vacuum — without fully understanding the challenges, needs, requirements, and timelines of all stakeholders — is a common mistake that leads to missed deadlines and costly rework.

Make the most out of each FDA interaction. Listen to and fully address their feedback.

FDA provides sponsors with multiple opportunities to seek their engagement, guidance, and support throughout the development process. It’s critical to take advantage of every opportunity for FDA interaction and to make the most of each of one.

Keep in mind that precision medicine is new to FDA reviewers, too. Precisely because the science behind these cutting-edge therapies is so new and evolving, the majority of these therapies have unknown safety profiles, utilize complex manufacturing technologies, incorporate new devices, and use cutting-edge testing methodologies. That means that FDA reviewers are facing a steep learning curve as they review cell and gene therapy applications. Gaining early input from FDA regarding the evidence and detail they’ll need to understand the risk-benefit profile of your specific therapy is essential to de-risking and accelerating the development process.
Be thoughtful about the timing of each FDA interaction. If you schedule these interactions too early and significant changes are made to your product development plan, you may create undue concern among FDA reviewers. On the other hand, scheduling these interactions too late in your timeline — for example, after you have completed POC and pilot/safety studies — may lead your meeting request to be denied. Another potential, and costly, risk of scheduling these interactions too late in the development process is that you may not have the opportunity to adjust your clinical studies to incorporate FDA feedback.
Prepare well; provide thorough information and ask compelling and relevant questions. This means providing full protocols for definitive studies and clinical trials and avoiding vague questions. It also means anticipating questions you might receive from reviewers and practicing how you would respond during the meeting.
Incorporate feedback from FDA meetings into your development plan, documenting how each piece of feedback has been addressed. This can be facilitated with a simple chart that tracks each FDA recommendation, how the recommendation was addressed, and wherein the eCTD the FDA reviewers can quickly find documentation that their feedback was addressed.

The FDA INTERACT meeting: An invaluable opportunity to accelerate the development

FDA will typically grant cell and gene therapy sponsors a single INTERACT meeting, during which sponsors can obtain initial, nonbinding advice from the FDA regarding chemistry, manufacturing and controls; pharmacology and toxicology; and the clinical aspects of the development program. This informal meeting should take place before any pivotal nonclinical studies but after you have a good understanding of the manufacturing process. If managed wisely and well prepared for, this meeting can prove invaluable in gaining FDA feedback regarding your product messaging and how well your data support your product message in the context of their risk-benefit determination. It’s essential to utilize this meeting to gain FDA insight regarding:

Your early product characterization and preclinical proof-of-concept studies
The development of new drug delivery devices
Early phase clinical trial design elements
Critical issues or deficiencies that you should be prepared to address before submission

Remember that accelerating development does not equal accelerated approval

Your IND can be placed on clinical hold by the FDA for several reasons, but upward of 90% of all clinical hold letters from the FDA cite insufficient information as the cause.1 If an IND is placed on clinical hold, the sponsor must wait 30 more days to receive a letter from the FDA detailing the submission’s deficiencies. Once the sponsor responds to those deficiencies, the 30-day FDA review clock starts again. On average, clinical holds add eight months to a sponsor’s development process — but some sponsors have experienced clinical hold delays of 48 months. That’s why more than 40% of development programs are terminated after being placed on clinical hold.2,3

The bottom line: Take the time upfront to ensure your application is complete — lest you risk far lengthier delays by submitting insufficient information.

Submit your application only when you have complete, clear, concise information. While the FDA officially has 30 days to review an IND, reviewers in practice only have about three weeks to conduct a thorough scientific review of your submission, resolve any potential hold issues and work with agency management to obtain support for their decision. Also, keep in mind that FDA reviewers are juggling multiple submissions — often more than 10,000 pages each — under compressed review clocks and across multiple stages of development. These realities underscore why sponsors are well served to tap the knowledge and guidance of outside partners who have deep experience in drug development, FDA interaction and the eCTD publishing and submission process; this helps to ensure that sponsors submit complete information, messaging is consistent throughout the application and all data are summarized clearly and concisely.
Avoid data dumping. While you do want your submission to be complete, you don’t want to include any information in your IND unless it’s necessary to FDA in making their regulatory decision. Doing so can increase the risk that the FDA will require you to answer more questions — which will only delay your path to approval.

Understanding the risk of submitting rushed or incomplete INDs

More than 90% of clinical hold letters from the FDA cite insufficient information as to cause
Sponsors face a 40% increase in the risk of a clinical hold without a pre-IND meeting
Clinical holds on average add 8 months to the development process — but they can add as much as 48 months
Greater than 40% of programs are terminated after being placed on clinical hold

Source: Cardinal Health