By Bruce Levine, Ph.D., Barbara and Edward Netter Professor in Cancer Gene Therapy, University of Pennsylvania; President, International Society for Cell & Gene Therapy
The tragic combination of infectiousness and lethality of SARS-CoV-2 and COVID-19 has been the greatest public health emergency of the past 100 years. But there is a way forward through science, discovery, translation, and execution. Challenges to cell and gene therapy developers have included disrupted supply chains, mandates to work from home and minimize onsite staff, research projects halted, clinical trials impacted, and scientific conferences cancelled, postponed, or converted to virtual formats. Where we are now in the response and management of cell and gene therapy development, depends in part on local case positivity and in part on academic institution or company practices.
Research laboratories, especially those in academia, have been severely impacted by COVID-19 distancing and work from home restrictions. Some staff and healthcare workers, especially in hot spots, may have been personally affected. Early in the pandemic, many labs were forced to shut down or operate with skeleton crews. For some researchers, this provided time to catch up on data analysis and manuscript writing. However, there has been disparity of impact even within laboratories. Graduate students and post-doctoral fellows with wet laboratory based projects have had to shut down and put those projects and their training on hold. Limits were placed on the number of personnel per research lab bay, common areas, conference rooms, and other spaces. Where infections have waned from peak in various locations, that has allowed a partial repopulation of laboratories, albeit with strict mask protocols and health checks or health questionnaires in place prior to entry. Work from home for those who can has been mandatory at the peak, and highly encouraged more recently. Video conferencing has filled some of the gap in communication within and among laboratories, though what continues to be challenging in the virtual environment is the by chance coffee machine conversations that often spark new ideas.
Academic facilities co-located within a medical complex must protect staff and especially patients. Cell and gene therapy clinical trial enrollment was affected mostly by a slowdown in enrollment by clinical sites, or patients deferring enrollment. As COVID-19 cases accelerated, institutions reduced in person visits and shifted to telemedicine. This did have impact on recruiting and scheduling visits for screening. Clinical teams also were mindful of the commitment in clinical trials for cell collection and infusions visits, as well as post-treatment sample collection visits. With cell manufacturing facilities adapting by converting to teams and shifts, demand has been able to be met. Personnel capacity controls of course have been in place, additionally, personal protective equipment and disinfection protocols have been enhanced. Adaptation has included redundancy in sourcing of many, but not all supplies. Academic medical facilities have also been able to multi-purpose infection control, patient protection measures, and testing developed for patients to extend to healthcare workers and laboratory staff. This includes the availability of first generation testing and now more rapid testing platforms. Messaging from institutions is critical and should be timely, accurate, transparent, and as comprehensive as current conditions allow.
Industry laboratories also prioritized critical and essential work, with some projects canceled or put on hold during peaks of transmission. Laboratory scheduling shifts for evenings and weekends and reconfiguration of equipment has helped to maintain distancing, with mandatory masking in place. Shift scheduling was also designed to help with work/life balance for employees who needed to be home during the day while in person schools and childcare were unavailable. Visitors have been restricted and some companies and institutions have been able to implement electronic registration systems for employees to track on-site presence, provide records if needed for contact tracing, and to record daily health questionnaires. Enhanced infection control measures including provision and wearing of masks, hand washing, cleaning of areas after use should be communicated frequently, reinforced and posted in key areas. Frequent communication via both email and company-wide virtual meetings is important to update staff as conditions change. Nevertheless, “Zoom fatigue” is real, and limits on videoconference hours to allow for individual work time should be considered.
The key to contingency planning, and ongoing management of laboratory operations during any pandemic is redundancy and resilience. By serendipity, the National Science Foundation funded Cell Manufacturing Technologies consortium (CMaT) had conducted a modeling study to simulate supply chain disruptions and published this in mid-2019 (ref1). The tests of the designed digital framework were to review an optimal reagent base stocking level, and to simulate a reagent supply disruption event. By understanding the impact of gaps in current supply chain, personnel, manufacturing facility continuity, and testing facility continuity, policies and standards can be designed to mitigate adverse impacts. Following the emergence of COVID-19, the simulation model was adapted to query the impact of supply chain and staff disruption on the priority queue for first in first out (FIFO) versus priority queue (PQ) patient product manufacture. The simulation model indicated that there are lower bounds to reagent availability and operator availability, which quickly trigger impacts on patient product manufacture. Priority queuing has only a modest impact on ensuring that adverse outcomes are mitigated (ref2).
Combinations of human interventions and digital simulations are tools for managing cell and gene therapy operations in time of acute or ongoing disruptions. Yet, these strategies do not operate in a vacuum. More than half a year (that seems like much longer) after the emergence of COVID-19, there is compliance fatigue, the persistence of mixed messaging from governments, continued risk of exposure in absence of the availability of a proven vaccine, economic disruption, with delayed timelines and impacts on funding runways. With the rush to develop potential therapies, cell therapy clinical development best practices are at risk. Rationally designed, controlled approaches to clinical investigation of cell therapies, and all therapies, are essential if safety and efficacy are to be demonstrated accurately (ref3).
Finally, although we are in the midst of the most devastating pandemic in the past 100 years, we have technological and drug development tools unsurpassed in human history. Dozens of vaccines and drug or antibody therapies are in clinical development, a variety of rapid tests have been deployed and more are on the way. We have clinical centers of excellence and we have robust pipelines of cell and gene therapies in development for patients in need. One need only to look to them, and the heroism of healthcare responders for inspiration. We cannot choose the times in which we live, but we can choose how we live and how we adapt within this time.
- Wang K, Liu Y, Li J, Wang B, Bishop R, White C, Das A, Levine AD, Ho L, Levine BL, Fesnak AD. A multiscale simulation framework for the manufacturing facility and supply chain of autologous cell therapies. Cytotherapy. 2019 Oct;21(10):1081-1093. doi: 10.1016/j.jcyt.2019.07.002. Epub 2019 Aug 21. https://www.isct-cytotherapy.org/article/S1465-3249(19)30818-7/fulltext
- Wang K, Liu Y, Li J, White C, Wang B, Levine BL, Modeling the Effects of Supply Chain and Operator Disruptions on Cell Therapy Manufacturing Facility Operations During the COVID-19 Pandemic. American Pharmaceutical Review, July/August, 2020 https://www.americanpharmaceuticalreview.com/Featured-Articles/567500-Modeling-the-Effects-of-Supply-Chain-and-Operator-Disruptions-on-Cell-Therapy-Manufacturing-Facility-Operations-During-the-COVID-19-Pandemic/
- Khoury M, Rocco PRM, Phinney DG, Krampera M, Martin I, Viswanathan S, Nolta JA, LeBlanc K, Galipeau J, Weiss DJ. Cell-based therapies for coronavirus disease 2019: proper clinical investigations are essential. Cytotherapy. 2020 Apr 17:S1465-3249(20)30616-2. doi: 10.1016/j.jcyt.2020.04.089. Epub ahead of print. https://www.isct-cytotherapy.org/article/S1465-3249(20)30616-2/fulltext