Fear Replaced by Understanding, Optimism, and Miracles: Part II
Accelerating the progress of cell and gene therapies with decentralized trials and other innovative approaches.
Daniel Eisenman | | 7 min read | Hot Topic
In part I, Daniel Eisenmann examined the evolution of cell and gene therapies from their early, controversial days in the 1970s to their current status as groundbreaking medical advancements. Here, he discusses the clinical trial process and how modern, decentralized approaches can further accelerate the field of cell and gene therapies.
After receiving an IND number for a new CGT trial from the FDA, the sponsor applies for institutional review board (IRB) approval to ensure the protocol conforms with regulations for human subject protection. If NIH support, in the form of funding or collaboration, is associated with a CGT trial, an independent institutional biosafety committee (IBC) review is also required at each research site to ensure compliance with NIH guidelines. Even if there are no ties to the NIH, the agency recommends voluntary compliance with NIH guidelines anyway. Often completed in parallel with the IRB review, IBC review assesses the unique risks posed by the investigational product to the caregivers, environment, research staff, and anyone else connected to the trial.
“Typically, sites are unaware of the intricacies around IBC reviews as few sites have much experience in cell and gene therapy trials in humans, but it is important. Where the IRB’s role is about protecting the patient, the IBC’s role is about protecting everyone else,” explained Megan Vaughn, associate clinical director at Krystal Biotech. “Filling out IBC application forms and interpreting molecular biology terminology can be very challenging, so we spend a lot of time hand-holding site staff through this process.”
IBC review can add time to the already long study startup process – but there are easy ways to avoid delay. Each site’s IBC must be registered with the NIH before the IBC can convene a meeting and issue approvals. However, the registration process can take up to eight weeks. The site’s registration is independent of the principal investigator or study and can be submitted in advance of winning a study. Sites interested in conducting CGT trials should register with the NIH upfront to avoid the delays.
In addition, sites can work with institutional IBC review providers with experience in CGT research to train research staff on unique complexities, including safety requirements and risk-mitigation strategies, specific to the requirements of the investigational CGT. Some companies offer databases of site networks that can help research sponsors to quickly and confidently identify appropriate sites ready to start a CGT trial on day one. Companies that offer remote inspection of sites in their databases also make it easy to continuously educate site staff on how to conduct trials safely while expediting study startup.
“Site staff who may not understand the complexity of gene therapy, the different types, and the potential risks greatly benefit from training by independent IBCs,” added Vaughn. “Otherwise, it is the responsibility of the sponsor or CRO to walk the site through the process, which can cause delays. We work with sites that are well-prepared and vetted to manage the complexities of CGT research because it increases efficiency, speed, and quality.”
Evolving Regulations
The FDA has taken important steps to help bring investigational CGTs from the realm of research to the world of approved therapeutics via a series of new guidance, collaborations, and accelerated approval pathways. Below are the major regulatory initiatives helping to move the field forward:
- The FDA has issued various guidance documents for the manufacture of gene therapy products and the design of clinical trials.
- The 21st Century Cures Act authorized the FDA to create the Regenerative Medicine and Advanced Therapies designation to allow for expedited review of regenerative medicines and advanced therapies. The associated guidance issued by the FDA stated the RMAT designation also applies to “gene therapies, including genetically modified cells, that lead to a durable modification of cells or tissues.”
- The FDA is expanding its capabilities to review gene therapy studies to accommodate the growing field. In a 2018 interview, FDA Commissioner Scott Gottlieb predicted the agency would approve 40 gene therapies by 2022; and in 2019, Gottlieb aimed to hire 50 additional clinical reviewers for CGTs. The goal was 10 to 20 gene therapy approvals per year by 2025.
- In 2023, the FDA launched a pilot program to help accelerate development of novel drug and biological products for rare disease therapies called Support for clinical Trials Advancing Rare disease Therapeutics (START). The agency invited several sponsors to engage more frequently with FDA staff to provide a mechanism for addressing clinical development issues.
- Also in 2023, the agency published a Request for Information for stakeholders to provide feedback regarding critical scientific challenges and opportunities to advance the development of CGTs designed for an individual or very small number of patients diagnosed with a rare disease. The agency plans to use this information to inform the planning, and ultimately facilitate the development of additional regulatory tools and/or frameworks.
- Most recently, the FDA created a specialized Office of Therapeutic Products, officially established in March 2023 as the first super office at the FDA’s Center for Biologics Evaluation and Research (CBER).
Modern technologies to accelerate progress
In parallel with the evolution of CGT science, digital and data technology have evolved. Combined, the two worlds can make magic happen. Here are three key disrupters:
- Decentralized clinical trial (DCT) technologies – Increased use of remote or digital technologies in hybrid and decentralized clinical trials affords geographically dispersed patients with greater opportunity to participate in trials. This is significant, especially, for rare disease trials where patients may be located hundreds of miles from the trial site. However, CGT trials may require extra oversight for patients and their caregivers, as well as additional site training so research staff know how to handle products safely. The FDA’s finalized guidance on DCTs is open-ended but, at the 2024 American Society of Gene & Cell Therapy (ASGCT), the Director of the FDA Center for Biologics Evaluation and Research said, “DCTs and gene therapy are not mutually exclusive,” suggesting that there is nothing prohibiting the use of DCT elements in CGT trials.
Sponsors will need to carefully consider the complexities of their trial to determine where, and if, a DCT element is appropriate and safe outside of an academic medical center. IBC review can help interpret early on whether administration of a drug can safely shift from site to home as there are cases when this is safe and a better option even for CGTs. - AI – Generative AI and large language models are already helping clinical research in various ways. For example, data intelligence providers can use causal AI to speed feasibility studies with predictive analytics. AI is already helping researchers accelerate drug discovery, too, but it is also helping in drug development, including the use of digital twin technology in lieu of a placebo, and trial-matching technologies. At the annual ASGCT meeting, the FDA noted the value of AI to quickly match trials to patients that would most benefit from them.
- Integrated trial platforms – technology has helped streamline many processes in clinical research, but the number of point solutions that do not ‘talk’ to one another is also increasing burdens for sponsors, CROs, and sites. Advarra’s 2023 Study Activation Survey shows 67 percent of sites say the technology burden is worse than just five years ago. With increased use of technologies comes a commensurate increase in logins for site staff – in fact, nearly 70 percent of respondents report having six or more logins per study. The good news is that technology providers are now addressing this issue with centralized, integrated platform technology and single sign-on solutions.
“Integrated platforms are very helpful,” said Vaughn. “There are so many administrative requirements for these submissions, so when we spend time tediously submitting the same document to multiple places, it steals time away from the science and helping patients.”
Striking the right balance
The CGT market is an evolving ecosystem. While the government seeks to streamline and support growth in this field, industry must remain vigilant about critical safety needs and clinical research risks. Striking a balance between accelerating progress and ensuring safety is essential – not only for the patients who need to be fully aware of potential risks but also for caregivers and research professionals handling these products.
Even as we seek to balance innovation and hope with prudence and real-world results, excitement is in the air. Over 85 new gene therapies across more than 12 disease states are slated to win regulatory approval by 2032, according to a report from Tufts Medical Center think tank NEWDIGS. To drive continued growth in this remarkable area of science, all stakeholders – from regulators to technology providers, from sites to sponsors – will be instrumental in providing the right building blocks for success.
Executive Director of Biosafety Services at Advarra where he directs Institutional Biosafety Committee and biosafety consulting services, helping researchers navigate regulatory requirements to ensure research is conducted safely and with minimal regulatory delay. Prior, Eisenman served as Biological Safety Officer for University of North Carolina at Chapel Hill, and the Medical University of South Carolina. He can be reached at [email protected].
