In the last decade, the number of approved gene therapies for the treatment of genetic disorders has increased rapidly. Currently there is a trend to adopt technologies that maintain safety and efficacy while reducing production costs during manufacture.
Navigating the complex and dynamic gene therapy regulatory landscape has been a persistent challenge for developers and manufacturers. Ensuring these life-changing therapies successfully pass critical regulatory milestones on the journey to market requires gene therapy producers and their partners to demonstrate both flexibility and agility.
With gene therapy being a fast-paced yet relatively new therapeutic area, regulatory bodies have struggled to keep up with continuous technological advancements and our expanding knowledge of genetics, virology and molecular biology. With no blueprint to follow, a practical approach has been necessary to ensure regulations and guidance can safeguard the quality, efficacy and safety of new therapies entering the market.
In this article, Kai Lipinski, Ph.D., Chief Scientific Officer; Xiaojun Liu, Director of AAV Process Development; and Jing Zhu, VP of Nucleic Acid & Virus Technology at ReciBioPharm, explore the current gene therapy regulatory landscape and provide their expert insights into the tactics developers and manufacturers must employ to overcome regulatory challenges.
For many years, researchers and developers have striven to realize the potential of therapeutics that introduce specific cells or genetic material to patients for disease treatment and prevention. Owing to breakthroughs and advancements in technology and genetic engineering in the last two decades, we are now at the dawn of a new cell and gene therapy (CGT) era.
There are currently 15 approved gene therapies and 12 cell-based immunotherapy products. Although the gene therapy space has come a long way since the first approved therapy in 1990, which utilized a retroviral vector to deliver functional adenosine deaminase genes, most gene therapies approved today still harness the delivery capabilities of viral vectors.
Viral vectors have proved to be efficient tools for gene delivery to specific target cells or tissues. Commonly used gene therapy viral vectors, including adenoviruses (AV), adeno-associated viruses (AAV), retroviruses (RV), lentiviruses (LV) and herpes simplex viruses (HSV), have unique characteristics that provide distinct advantages for gene delivery. For example, AAVs are ideal for in vivo gene therapies due to their mild immunogenicity. Integrating viruses such as LVs are useful for ex vivo treatments like CAR-T therapies, where genes must be stably integrated into the host cell genome to enable long-term expression.
As our understanding of genetic engineering has grown, the safety and efficacy of gene therapies have advanced, in part owing to improvements in viral vector construction and the creative use of pseudotyping to increase cell or tissue specificity.
Advancements have enhanced not only the safety and efficacy of viral vector-based gene therapies, but also their manufacturability. The application of single-use technologies (SUTs), the development of stable packaging and/or production cell lines and the progression of analytical equipment have all played an important role in furthering manufacturability. These improvements have helped to broaden access to gene therapies.
Although the first FDA gene therapy approval was only in 2017, CGTs have garnered a significant amount of investment in this short time. In part, this has been driven by the increasing recognition of the potential of gene therapies. The number of these revolutionary drugs entering the development pipeline targeting various indications, from rare diseases to cancer and metabolic disorders, is continuously growing.
Propelled by a desire to broaden patient access by reducing manufacturing costs and technical limitations of viral vectors, gene therapy developers are also increasingly looking towards non-viral options, including nucleic acid delivery platforms. As a result, there is a growing desire to use innovative technologies such as engineered lipid or protein nanoparticles, DNA-based nanocarriers and novel physicochemical methods in gene therapies.
Reflecting the expanding potential of gene therapies, the global gene therapy market is predicted to continue to grow rapidly. Valued at USD $5.6 billion in 2022, the market is expected to reach USD $49.3 billion by 2032, registering a CAGR of 25%.
Despite this promising outlook and continued improvements in safety, efficacy and manufacturability, the number of gene therapy product approvals has been slow to rise, with only four such therapies gaining FDA approval in the five years prior to 2022. Factors that have contributed to this include:
● Communication issues between sponsors and the FDA/EMA
● A shortage of qualified specialist staff owing to the gene therapy space being relatively new
● Economic headwinds and investors being selective in their capital allocations
● High manufacturing costs and small patient populations
● Manufacturing bottlenecks
In spite of these challenges, 2022 marked a turning point for gene therapy FDA approvals, with five achieved by the end of the year, including therapeutics targeting rare diseases and cancer indications. Looking ahead, close to 20 CGTs are now set for a regulatory decision in 2023. As a result, we could be within reach of the FDA’s 2019 prediction of approving 10-20 new CGTs a year by 2025.
However, there are still several difficulties gene therapy developers and manufacturers face when navigating the complex regulatory landscape. These challenges must be carefully addressed to enable potentially life-changing therapies to reach patients.
There are currently 2,022 gene therapies (including genetically modified cell therapies such as CAR T-cell therapies) in development, 284 of which are at phase 2, phase 3, or pre-registration. The approximate success rate for CGTs from phase 2 through to approval is only 14%. This is less than half of the expected success rate of small molecule drugs from phase 2 (43%), highlighting the difficulties CGTs face on the journey to market.
Meeting the FDA’s 10-20 new CGT approval target will require developers and manufacturers to understand, navigate and overcome various challenges. The most pressing of these include:
1) Compliance difficulties, with regulatory agencies “building the plane as it flies”
A recent survey revealed that dealing with confusing regulatory guidelines was considered one of the top obstacles developers face when bringing a CGT to clinic5.
As CGT is a relatively new therapeutic space, the understanding surrounding it has quickly expanded. Regulatory bodies have had to react quickly to this new information and provide guidance on best practices to ensure safety and quality. This has been compounded by the fact that CGTs are an order of magnitude more complex than small molecule therapeutics and traditional biologics, like monoclonal antibodies.
2) Caution in the approval process leading to stringent requirements
As gene therapies have advanced, the regulatory requirements surrounding their production have become increasingly rigorous. The fact that gene therapies typically involve genetic manipulation and have long-lasting effects has driven regulators to be more cautious in their review of these drugs to safeguard against unpredictable effects on patient health. This wary approach to reviewing gene therapies may slow down the approval process.
Regulatory body caution also stems from the limited available clinical trial data surrounding long-term safety and efficacy due to gene therapy being a relatively new field. The resulting difficulty in assessing the risks and benefits of a new gene therapy can lead to further delays in the approval process.
3) Unique analytical conditions adding complexity in meeting regulatory requirements
For both clinical trials and commercial gene therapy use, developers and manufacturers must provide extensive analytical data and evidence to regulatory bodies to demonstrate compliance. Meeting the analytical needs of gene therapies is often more difficult compared with traditional biologics because:
● The analytical tests required for traditional biologics like monoclonal antibodies (mAbs) have been around for years and are well understood and established
● Guidance surrounding gene therapy analytical testing is limited
● Gene therapy analysis often requires the adapted use of equipment techniques originally designed for traditional biologic analysis purposes, including potency assays to full/empty particle ratio analysis and genome DNA heterogeneity analysis
● The need for cell-based assays, particularly for assessing potency and infectious titer that can take weeks to perform, potentially slowing project progression
4) Manufacturing issues impeding dose needs as projects scale
As gene therapies are typically complex, they require specialized manufacturing processes, including introduction of viral vector and helper genes/plasmids to the production cell line (typically HEK293 cells) through transfection. In addition to creating unique challenges, these processes can be difficult to scale up. This can lead to difficulties in manufacturing enough doses to meet the demand at various stages as the project progresses, potentially slowing the timeline to critical milestones and regulatory approval.
Despite the difficulties gene therapy developers may face ensuring regulatory compliance, it is important to remember the FDA’s goal is to increase the number of gene therapy approvals, but not to the detriment of patient safety. Although maintaining diligence in ensuring therapeutics are safe and of high quality, the FDA is making changes to enable a greater number of approvals in the future, including:
Establishment of specialized “super offices”
A fundamental challenge the FDA has faced in meeting its goal to approve 10-20 CGTs a year by 2025 is understaffing. This lack of personnel has made it difficult to progress therapies swiftly through the review process. In March 2023, the Office of Therapeutic Products (OTP) was established as the first “super office” at the FDA’s Center for Biologics Evaluation and Research following reorganization. By centralizing departments involved in the review, inspection and research of CGT drugs, the OTP could streamline workflow processes while creating flexibility and capacity to increase employee numbers.
New initiative launches to strengthen communication
In the past few years, the FDA has launched a number of programs to help grow the gene therapy pipeline and provide opportunities for developers and regulators to communicate more frequently.
Serving as a traffic light system for the progression of small-batch gene therapy programs, the Bespoke Gene Therapy Consortium (BGTC) is an effort to remove barriers and streamline processes for these projects. The BGTC will achieve this by providing details on basic and clinical research, manufacturing, production and regulatory needs to gene therapy producers.
Additionally, the FDA’s INitial Targeted Engagement for Regulatory Advice on
CBER/CDER ProducTs (INTERACT) meeting program aims to facilitate IND-enabling efforts where the sponsor is facing a novel, challenging issue that could delay product progress towards clinic entry. The INTERACT meeting program could help to address issues early in development programs and prevent delays in initiating or progressing IND-enabling studies.
The recently launched Gene Therapy Pilot Program will also provide gene therapy developers with real-time FDA input throughout the clinical development process. This could enable shorter development cycles and submission review timelines.
Although these changes provide promise in achieving the FDA’s approval goal by 2025, the FDA cannot meet the need for new gene therapies alone. Drug developers and manufacturers must know how to navigate the regulatory requirements set to demonstrate gene therapy safety, efficacy and quality to ensure successful approval and delivery to patients.
Gene therapy developers and manufacturers should employ a number of tactics to ensure regulatory compliance while accelerating timelines to approval.
Communication is key
Ensuring compliance with often confusing and complex gene therapy regulatory guidelines can only be achieved if drug developers and manufacturers are aware of and understand them. Prioritizing open communication with regulatory bodies will ensure clarity and prevent possible mistakes caused by misunderstandings.
Proactively communicating with the FDA is particularly important before IND submission. By arranging pre-IND meetings with the FDA, developers can reach an agreement on the proposed animal safety and toxicology testing needed to support the phase 1 clinical trial design. This is particularly helpful to those with little or no prior IND submission experience.
Keep up with analytical advancements
Cutting-edge analytical capabilities are often needed to overcome the difficulties involved in gene therapy analytical characterization. Regulatory bodies can also be expected to continue requiring developers to meet stringent analytical demands surrounding the demonstration of gene therapy safety, potency and efficacy.
To meet these analytical needs, it will become increasingly important for gene therapy developers to employ novel options and sophisticated techniques in their analytical development. These include digital PCR, flow virometry (e.g., Sartorius, ApogeeFlow, NanoFCM), virus mass photometry, interferometric microscopy or multi-angle dynamic light scattering.
In the coming years, we can expect new insights — including those around the cause of possible side effects and lack/loss of stable efficacy — to continue to influence regulatory guidelines. Gene therapy developers and manufacturers must stay abreast of guideline changes and predict the changes to come, as much as possible. To respond quickly to changes in regulatory requirements and rising demand for gene therapies, their producers will need to continue to adopt new technologies. These technologies will include SUTs, continuous processing and perfusion-based cell culture for process intensifications.
With increasing innovation in virology and genetic engineering, the future of gene therapies looks bright. As these revolutionary therapeutics venture into new therapy areas and address the needs of wider patient populations, regulatory bodies must continue to respond to advancements. By producing guidance reflecting these changes, the safety, efficacy and quality of gene therapies achieving approval can be assured.
Meeting the FDA’s ambitious future approval goals will require changes not only on the part of regulatory bodies — to reduce delays — but also on the part of drug developers and manufacturers — to adapt their processes with these changes in mind. With so many moving parts, strong communication between gene therapy producers and regulatory bodies is expected to be increasingly important.
2. Gene, Cell, and RNA Therapy Landscape Q1 2023 Quarterly Data Report. American Society of Gene and Cell Therapy.
3. Sheridan C. Why gene therapies must go virus-free. Nat Biotechnol. 2023 Jun;41(6):737-739.