Regulatory Focus, July issue: Cell and gene therapy

Feature ArticlesFeature Articles
| 02 August 2020 | By Renee Matthews  | ©

Feature articles during July focused on global regulatory strategy for cell and gene therapy, with articles on US and EU regulations and guidances and the development and manufacture of the therapies. Also included were articles on recasting the corrective and preventive action (CAPA) process as a continuous improvement process, a military-civilian perspective on real-world evidence (RWE) to support regulatory decision making, and regulatory reporting in multinational trials during COVID-19.
Advanced therapy medicinal products (ATMPs), including cell therapies, gene therapies, and tissue-engineered products, are highly complex treatments that differ from traditional medicines, both in how they are made and administered and in the benefits they may provide. Regulations for these products were established relatively recently and are still evolving in many jurisdictions globally. The novelty of these products, the inherent complexities of cell and gene therapy products, and the lack of experience with such products pose many challenges for developers.
In part one of this two-part series, this month’s expert authors address these challenges and offer hands-on, practical advice and guidance on regulation and production of ATMPs. If there is one clear, take-home message to developers, it is that early and frequent collaboration with regulatory agencies, during both the approval and development phases, is paramount. It saves time and money, and it reduces the risk of a negative impact on the trajectory of a clinical trial. Part 2 of the series will cover upstream manufacturing and process controls for biologics, the ATMP regulatory landscape in China, EU GMP requirements for autologous cell therapies and parenteral biologics, and regulatory challenges and opportunities in the US.
Regulations and guidances
The regenerative medicine advanced therapy (RMAT) field has the potential to provide profound benefits to patients with serious diseases and disorders, and the RMAT designation is helping drive these transformative technologies to market. In Update on RMAT designations, William K. Sietsema and Janet Lynch Lambert discuss the scope and purpose of the special designation for RMATs created by the passage of the 21st Century Cures Act and provide a tally of products that have received the special designation to date. However, while the promise of regenerative medicines to cure disease is propelling the field at a rapid pace, developing these therapies requires a rigorous, carefully planned approach to ensure a seamless progression to regulatory approval and commercial success.
Siegfried Schmitt expands on that point about carefully navigating the complex and nuanced regulatory environment in two articles on US and EU regulations for RMATs and ATMPs, respectively. In US regulations for regenerative medicine advanced therapies, he provides a user-friendly, quick-access list of RMAT-related regulations and guidances. The article includes a useful introduction to the application process and descriptions of the features and criteria for various expedited program options, including breakthrough therapy, fast track, advanced approval, and priority review.
In Regulation of advanced therapy medicinal products in the EU, Schmitt explains some of the terminology relating to ATMPs before documenting the key EU regulations and guidances for each therapy type. He concludes with discussions on marketing authorization, accelerated regulatory pathways, and market access. Again, he urges companies and developers to engage with the regulatory agencies early and often throughout the approval process and to seek external regulatory support, especially if the developer has limited in-house regulatory resources.
Development pathways and manufacturing
Two articles shift the focus from the regulatory landscape to development and manufacturing pathways. The drug manufacturing facility environment presents one of the major sources of potential contaminants in the final biologic drug product, so it is critical to design facilities with cleanroom environmental controls and monitoring that adhere to the highest standards of current good manufacturing practice (cGMP) quality guidelines, write Mo Heidaran and colleagues. In Designing a biologics manufacturing facility: Early planning for success, the authors lay out the planning steps for compliance with cGMP to readiness for chemistry, manufacturing, and controls (CMC). The authors warn that the pressure to reduce time to market put considerable stress on all aspects of commercial operations and commercial-scale manufacturing development, so yet again, early tactical and strategic planning essential.
In Advanced therapies: ‘Trip hazards’ along the development pathway, Kirsten Messmer and Richard Dennett focus on the challenges and complexities of ferrying advanced therapies along the developmental pathway, which they call “the trip.” They examine the importance of some of the fundamental building blocks for the development program and highlight some commonly encountered challenges, or “trip hazards,” for cell and gene therapies. The suggest developers establish sound technical and regulatory strategies to better anticipate and avoid the trip hazards, which could prove costly, both in time and money, and have a negative impact the overall clinical study program.
Today’s CAPA process has become highly focused on compliance, which has manufacturers struggling to determine which issues require a structured CAPA process and which can be resolved in alternative ways, writes Kathryn Merrill in Recasting CAPA as a continuous improvement process. Merrill summarizes a white paper developed by the Medical Device Innovation Consortium, in which the CAPA process is recast as a continuous improvement process for driving higher product quality and improved patient safety. It is intended to enable organizations make a greater number of improvements more quickly, and over time, which will have a favorable impact on product quality in the field.
During the Afghanistan and Iraq wars, the US Military Health System used an approach known as “focused empiricism” to develop new approaches for casualty care. In doing so, it implemented real-world data (RWD) and RWE into a system of performance improvement and product development to achieve historic rates of survival, write Todd E. Rasmussen, a colonel in the US Air force, and Brian J. Young. In A military-civilian perspective on real-world evidence to support regulatory decision making, the authors summarize the framework promoting the collection and analysis of RWD in the healthcare system and describe a new era of collaboration between the US Department of Defense and the FDA, within the context of a new Public Law 115-92, to coordinate on the delivery of military-relevant medical products. The article reviews the FDA evidentiary standards for medical product approval and gives examples of how RWE can help meet those standards.
COVID-19 continues to disrupt and redefine the regulatory process and activity. In Managing uncertainty: Regulatory reporting in multinational trials during COVID-19, Ioana Ionita discusses regulatory reporting challenges for multinational clinical trials during the pandemic, as well as the challenge of assessing what is reportable and how to submit COVID-19 risk mitigation measures. She offers real-world experience on how she and her colleagues stopped and restarted recruitment in ongoing multinational clinical trials, and how those actions were reported globally. Ionita concludes that close collaboration between sponsors, CROs, local affiliates, investigational sites, and health authorities is important in choosing strategies under challenging circumstances and when no precedent applies.
What’s coming in August?
Articles during August will focus on global clinical trials and clinical trial applications. Despite ICH efforts to produce guidelines for the development of drugs and biologics and to standardize the format of marketing applications, there remain considerable differences among countries in the format of clinical trial applications and health authority review processes. This collection of articles will address these divergent formats and processes and provide options for navigating the regulatory aspects of clinical trials. Look for these topics and more throughout August at
October call for articles
For October, Regulatory Focus will look at the regulatory toolbox—the tools regulatory professionals need and where to find them, with an emphasis on websites, guidances, meeting minutes and FDA correspondence, including warning letters, enforcement actions, 483s, and notices. Articles will discuss how to interpret the meaning behind regulatory agency actions and available options for documentation. The submission deadline for articles is 1 September 2020. To contribute to the October issue or suggest a topic, contact Renée Matthews at
Citation Matthews R. Regulatory Focus, July issue: Cell and gene therapy. Regulatory Focus. July 2020. Regulatory Affairs Professionals Society.


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