March 05, 2021
Note: This article originally appeared in the February 2021 issue of AABB News, a member benefit of AABB.
By Leah Lawrence
The age of clinical trials designed to test the transformational potential of gene and cellular therapies has arrived. A 2019 report by the Alliance for Regenerative Medicine estimated that there were more than 1,000 clinical trials underway worldwide to test gene therapy, gene-modified cell therapy, cell therapy and tissue engineering.1 Given this rapid evolution, staff at cellular therapy laboratories seeking to participate in these endeavors have to be well-versed in the clinical trials process.
However, there is really no established process for how best to do this.
“Every institution functions differently so there will not be a one-size-fits-all approach,” said Yvette C. Tanhehco, MD, PhD, MS, assistant professor of pathology and cell biology at Columbia University Irving Medical Center. “It would be helpful though for there to be some sort of general guideline or recommendations that labs should consider when developing their own protocols.”
The Role of the Lab
In 2017, the U.S. Food and Drug Administration approved the first gene therapy – tisagenleceucel (Kymriah) – for certain pediatric and adult forms of acute lymphoblastic leukemia.2 In the announcement of the approval, then-FDA Commissioner Scott Gottlieb, MD, heralded the entrance into a “new frontier in medical innovation” with gene and cell therapies that had the “potential to transform medicine.”
Buried on page six of the Supplementary Appendix of the 2018 New England Journal of Medicine article on the phase-2 trial that led to this approval are details about the manufacture of this transformational gene therapy product.3 A one-sentence explanation details that clinical site labs collected and cryopreserved autologous leukapheresis products and shipped them to manufacturing facilities.
This is a simple explanation for what is actually an immensely detailed process, according to Tanhehco. This represents one of the two models that exist for cellular therapy lab participation in the trial process. “The first is where the lab acts as a pharmacy,” she said. “The other model is where the lab actively participates in the manufacturing of the product.”
In a 2017 Transfusion article, Tanhehco detailed how her lab at Columbia University transitioned from the first model to the second, and the subsequent inundation of requests from clinical trials coordinators to participate in clinical trials sponsors by industry or academia.4
“It quickly became apparent that we needed a process to stay organized,” she wrote in the article.
New Partnerships, New Challenges
The ultimate goal of any cellular therapy being researched is eventual clinical use, said Suzanne R. Thibodeaux, MD, PhD, laboratory medical director, Cellular Therapy Laboratory, Barnes-Jewish Hospital, St. Louis, Missouri.
“When we see clinical trials product, we view them with that in mind and want to do our part to make sure the product is safe from a clinical aspect,” Thibodeaux said.
Lab leadership is in charge of helping to vet and coordinate each new trial partnership that is considered, Thibodeaux said. The lab’s first priority is always going to be handling all of the standard-of-care products, and clinical trial volume has to be considered as one small piece fitting into that larger puzzle.
“Developing questions to ask every study sponsor can help to establish a systematic way to evaluate whether or not the lab can handle each new trial,” Thibodeaux said. That is because each trial sponsor may have a varying set of requirements, she said.
“Each clinical trial may have developed its own separate protocols, but the cellular lab itself may also have its own protocols and processes,” Thibodeaux said. “That becomes a point for discussion. Both parties must be open-minded and willing to discuss what can reasonably be done.”
Questions to Ask
This discovery process may begin with some high-level questions, such as establishing contact information for the principal investigator, the research coordinator and the study sponsor. Other high-level information to gather includes the study title, sponsor, sponsor type, phase, services and testing required from the lab, and how services will be billed.
“We also ask about the timeline of the study. How soon it will start and how long it will last?” Tanhehco said. “It is typically best for us to stagger start dates of trials to better manage our resources.”
Questions should also cover how many patients are expected to be enrolled total and how many each month. However, once these high-level questions are addressed, there are also many more detailed logistics that will have to be established, explained Sandhya R. Panch, MD, MPH, medical director of the Center for Cellular Engineering at the National Institutes of Health (NIH).
If it is a lab that will mainly be involved in apheresis collection, shipping and receiving, it should gather information on shipping. Who is paying for the shipping? What kind of raw material is needed? What time frame will samples need to be shipped? Does the final product come back frozen?
“These details matter. For example, one important detail that people often miss is that these products often come back frozen in a cassette that goes into liquid nitrogen tanks,” Panch said. “You have to ask what size these cassettes are to know if they will fit on your racks. I encourage facilities to think this through, especially if they are working with several trial groups.”
Martin Ongkeko, MD, a senior clinical fellow in the NIH’s Center for Cellular Engineering, participates in meetings to develop protocol-specific instructions (PSIs) for clinical trials as well as other activities that include discussions of new protocols with clinicals teams.
He helps prepare PSIs for the handling of products from contract manufacturing organizations (CMO) based on cellular therapy manuals provided by the CMOs, which may differ for each trial.
During the pre-study planning phase, meetings are set up between the principal investigator and the clinical team, the Center for Cellular Engineering, and the CMO early in the stage of development to discuss logistics. Key personnel included in these meetings are medical directors,
service coordinators, manufacturing team supervisors and quality assurance representatives, Ongkeko said.
“Adjustments in both the Center for Cellular Engineering in-house procedures and study-specific instructions always have to be made; the feasibility of such alterations, the steps to be taken and the timeline for the protocol are outlined,” Ongkeko said. “The entire manufacturing process has to be considered in these meetings, including details related to the study design, dosing information, product types to be collected, manufactured and issues, summary of processing instructions, samples to be submitted for assay testing, product container and accompanying labels, product release, instructions for thaw, distribution and administration instructions and laboratory management software instructions.”
Ongkeko said that they try to avoid too many alterations to existing operations; however, minor changes may be required with each trial. He then leads a weekly meeting to gather consensus and develop the PSIs. Once these are developed and staff are trained, a mock run will be performed.
A mock run or mock shipment was also suggested by Tanhehco. This process allows for the identification of issues in the trial process.
Planning for clinical trials must also include consideration of the lab’s workflow. This will be particularly important, Thibodeaux said, as the number of clinical trials that include cellular therapies continues to increase. “By and large, our cell therapy staff level remains steady,” she said. “That is something we consider when we coordinate the ‘when’ of trials and look at when these products will be processed. We do it in a way such that existing staff can reasonably maintain safety and quality of all of our products , as well as their well-being as individuals and a group.”
Panch said that planning ahead is crucial for effective personnel coordination. Staff requirements can be estimated by looking at the types and volume of procedures expected and the projected volume throughout the course of a trial, she said.
“In the planning there may be penalties for not meeting laid out requirements or for cancellations because then we can’t plan our staffing accordingly,” Panch said. “Unfortunately, due to the nature of cell therapy, cancellations happen, but carrying penalties helps so that the facility does not take a huge hit by over staffing and underproducing.”
Guidelines and Tips
There are currently no established guidelines or recommendations available to help cellular therapy labs prepare for clinical trial participation.
“This can be frustrating,” Tanhehco said. “There are efforts to get industry partners to standardize to make things easier for labs, but that is ongoing.”
This standardization should be a priority though, she added, to ease the burden on labs. “It is hard on labs to spend a day or a day and a half sitting with auditors and inspectors before the trial on top of regulatory audits and inspections,” Tanhehco said. “Imagine doing that when partnering with 30 companies or 30 trials and undergoing that every year.”
Tanhehco and Panch have both published papers in Transfusion outlining some of the best practices at their institutions,4,5 and Thibodeaux and Ongkeko had some top tips to offer labs looking to get involved or increase involvement in clinical trials.
The top tip on both of their lists was communication. “Open up the lines of communication and keep them open,” Thibodeaux said. “Finding a way to incorporate regular communication into your systematic approach to clinical trials will help to keep your lab informed and help to ensure success.”
Effective communication means making sure that all the right shareholders have a seat at the table, she said. “At our institution there is a group formed where everyone involved in the process can discuss what trials are being considered, what trials are upcoming, which are ongoing and which are winding down,” Thibodeaux said. “That helps everyone be on the same page.”
At the Center for Cellular Engineering, that includes the clinical team, CMO, apheresis unit, manufacturing technologists, laboratory staff and shipping companies, Ongkeko said. “Communication is key to establish expectations and timelines with all teams involved,” he said.
Ongkeko also emphasized the importance of mock runs, calling them “indispensable.” Mock runs can identify issues that may not be readily identified during planning and strengthens staff confidence when actual products are manufactured, he said. He also encouraged labs to plan for scenarios where things do not go as planned.
“Hopefully guidelines can be formed sooner than later so we can all become better at handling trials now and in the future,” Thibodeaux said. “Cell therapy is clearly a part of patient care that is only expected to grow and labs being able to grow along with it will be beneficial for everyone.”
1. Alliance for Regenerative Medicine. Q3 2019 Data Report. https://alliancerm.org/publication/q3-2019-data-report/. Accessed February 19, 2021.
2. U.S. Food and Drug Administration. FDA approval brings first gene therapy to the United States. August 30, 2017. https://www.fda. gov/news-events/press-announcements/fda-approval-brings-first- gene-therapy-united-states. Accessed February 19, 2021.
3. Supplement to: Maude SL, Laetsch TW, Buechner J, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med. 2018;378:439-48. DOI:10.1056/NEJMoa1709866. https://www.nejm.org/doi/ suppl/10.1056/NEJMoa1709866/suppl_file/nejmoa1709866_appendix.pdf.
4. Tanhehco YC, Schwartz J. How we manage clinical trials in the cellular therapy laboratory. Transfusion.2018;58:8-15.
5. Chen LN, Collins-Johnson N, Sapp N, et al. How do I structure logistic processes in preparation for outsourcing of cellular therapy manufacturing? Transfusion. 2019;doi:10.1111.trf.15349.