Advancing Policy To Improve Safety And Efficacy For Cell And Gene Therapies

By Life Science Connect Editorial Staff

As advancements in technology, science, and workflows continue to open up potential within the cell and gene therapy space, issues have likewise emerged around scaling, policy development, pre- and post-approval monitoring, and other factors influencing the ultimate success of a therapy. The current workflows that support these modalities are time-consuming and present challenges for auditing and quality control. While global regulators demand tight control over these products, one of the common goals shared among researchers, clinicians, industry, and regulators is to improve workflows to better translate these therapies into safe and effective options to improve patients' lives.

In a recent installment of Cell & Gene Live, experts Nimi Chhina, Ph.D., JD, executive director, head of global R&D and regulatory policy global regulatory affairs, worldwide research & development at BioMarin Pharmaceutical, and Bob Pietrusko, Pharm.D., chief regulatory & quality officer at Vor Biopharma, explored the key variables in a CGT workflow that serve to impact patient safety, as well as the factors that most influence manufacturing decision-making in the current landscape.

The Importance Of Comparability

Establishing comparability is one of the fundamental factors cell and gene therapy companies must prioritize when working to achieve regulatory acceptance. Earlier this year, the FDA released draft guidance aimed at addressing the unique variables that impact cell and gene therapy manufacturing, built upon existing recommendations for comparability and manufacturing change management for biologics. The purpose of Manufacturing Changes and Comparability for Human Cellular and Gene Therapy Products is to afford drug developers more tailored insight into the FDA’s expectations for the management and reporting of manufacturing changes for cell and gene therapy products based on life cycle approaches. This includes approaches to scale up and comparability studies that adequately assess the effect of resulting process changes on product quality.

The potential risks and pitfalls that accompany cell and gene therapy products are, in many cases, amplified when compared to other drug products. As such, these complex and delicate modalities require careful planning around manufacturing change assessment to avoid serious impacts to safety and efficacy. Existing guidance, such as the FDA’s 1996 guidance on demonstrating comparability for human biologics products, as well as the ICH’s Q5E guidance issued in 2005, are valuable resources for many core principles relevant to conducting comparability studies, but their limited scope and applicability for proteins more easily purified and characterized make them helpful largely in informing a more basic framework for comparability. Ultimately, the more specific recommendations outlined in the FDA’s 2023 guidance, combined with a comprehensive, end-to-end approach to comparability planning, are critical to addressing the manufacturing needs of these sensitive, costly therapeutics.

Identifying Risk And Establishing Comparability Early (And Often)

The first step in establishing a framework for comparability is conducting a risk assessment. A solid risk assessment approach will delineate any potential impacts of manufacturing changes on all discrete manufacturing steps affected, as well as the in-process parameters downstream of any manufacturing change. If the risk assessment reveals the need for a comparability study, the next step for sponsors is to outline a stepwise approach that identifies all quality attributes and process parameters to be evaluated in a comprehensive comparability study. Sponsors should determine the attributes affected by a particular change, assigning a score to each based on the probability, severity, and detectability of the risk.

For any manufacturing change that could result in an impact on product quality, a protocol amendment must be submitted to the FDA. This documentation requires a thorough examination of the underlying science supporting the change and its effects on product characteristics, particularly safety, identity, quality, purity, and potency. When dealing with living cells, even minor changes in variables such as temperature or culture media can have dramatic impacts on cell performance and product safety. This means that any change requires a close examination of the affected process parameters – for example, does a change in temperature affect the length of a product’s resting cycle? To this end, looking beyond a product’s release qualities to more far-reaching characterization studies can help support more proactive regulatory engagement.

Working To Further Safety Through Standardization

While achieving comparability during development is important, another key hurdle that can impact a product’s ultimate success is navigating post-approval changes. One of the biggest challenges the cell and gene sector has encountered in this respect relates to its relative infancy – the novelty of many of these advanced therapeutics has meant that the industry is still struggling to clearly tie quality attributes to clinical outcomes. As a result, achieving in vitro comparability is difficult, and sponsors are often required to pursue supplementary, non-clinical in vivo animal data or other clinical data. This challenge likewise underpins the importance of identifying and controlling the analytical suite used to characterize these drugs early in development. This, coupled with continued efforts to achieve greater foundational scientific insights that link CQAs to safety and efficacy, will be decisive in reducing workflow risks for these modalities.

Many of the cell and gene products in development today undergo gene editing to achieve more targeted effects. These edits can introduce off-target effects that are challenging to identify and that can have hugely detrimental effects for patients – several products, after entering the market, have been reported to produce malignancies in patients. Achieving continuous monitoring for this sort of risk potential to determine root cause is key; in particular, keeping attuned to products on the market and working to identify potential causes in the preclinical phases will be crucial to improving patient safety and addressing off-target effects.

Pursuing Policy That Prioritizes Patients

As the science evolves regarding advanced therapies, so, too, will policy aimed at supporting safer, more proactive drug development. The Prescription Drug User Fee Reauthorization Act (PDUFA VII) augmented the FDA’s cell and gene therapy program with additional resources for the Center for Biologics Evaluation and Research (CBER) to sustain and expand its reach. This expansion has enabled CBER to heavily pursue policy development, public-private partnerships, and education for the public. Much of cell and gene therapy development now falls under the PDUFA umbrella; for example, INTERACT meetings are now managed under PDUFA, and a new meeting type, known as “D” meetings, was created to handle discussions related to potency. Additionally, new commitments related to rare diseases, including a new rare disease endpoint advancement pilot, have been established under PDUFA and apply to many advanced therapies currently in the pipeline. Another new PDUFA commitment is focused on the tools and methods used to capture patient experience data to inform regulatory decision-making; moreover, FDA has committed to pursuing draft guidance on evaluating the efficacy of these drugs in small patient populations, using novel trial designs, to inform similar methodologies for more common diseases.

Importantly, the FDA, under PDUFA VII, has committed to issuing draft Q&A guidance that addresses frequently asked questions and commonly faced issues identified by sponsors or by public-private partnerships. It is also tasked with updating its guidance surrounding the regenerative medicine advanced therapy (RMAT) program, particularly for post-approval requirements. This revision will chiefly address the use of real-world evidence (RWE) to confirm the clinical benefits of products designated for accelerated approval, as well as best practices for safety monitoring and follow-up. Finally, the FDA has also committed to convening a public meeting with manufacturers to identify how sponsors can leverage internal, prior, and public knowledge to support more standardized manufacturing across the sector.

Outside PDUFA VII commitments, FDA has likewise promised to pursue draft guidance surrounding platform technologies. While this guidance will apply broadly to pharmaceutical manufacturing, it is likely to cover cell and gene therapies and offer insights unavailable in other guidance documents. Other forthcoming guidance to watch for includes new potency guidelines, voluntary consensus standards, and considerations for the use of human and animal derived materials and components in the manufacture of cell and gene therapies and tissue engineered products.

Another crucial consideration for cell and gene therapy development is the use of clinical outcome assessment tools and digital health technologies. These tools can enable decentralization of clinical trials, which is often invaluable for cell and gene therapy development, particularly for rare disease research. These technologies can also enable more long-term monitoring, which is crucial for sponsors working to be proactive in identifying and mitigating issues through post-approval changes. Patient registries collecting longer-term RWE will be critical to establishing more standardized and safer manufacturing practices for these modalities; partnering closely with FDA to share data to inform regulation will likewise be important for informing future policy.

Conclusion

Ultimately, establishing a dialogue between sponsors and the FDA and encouraging more information-sharing across the industry will help to cultivate greater control over the safety and efficacy of these products. Policy development for cell and gene therapies will continue to be driven by the complexity and unique characteristics of these products; the diversity of the assets that fall under the advanced therapy umbrella is likely to inspire more class-specific policies in the future. Achieving greater specificity for cell and gene therapy guidance is crucial, but even more crucial is establishing guidance informed by patient experience. Patient perspectives have historically been one of the most fundamental influences informing FDA guidance; continuing to prioritize this perspective through technologies and approaches optimized to capture patient data will be key to driving new insights and informing better policy in the years to come.