Insights from CGTW16 – Part 3: Clinical trials, health economics and regulatory affairs

Author: Guest, 12/01/16

Amin Adibi is a biomedical engineer and a research assistant at the University of British Columbia. His areas of interest include cell manufacturing and bioprocess optimization, clinical translation of cellular therapies, health outcomes and cost-effectiveness modelling. Amin has an MSc degree from University of Calgary, where he focused on developing adjuvant MSC-based therapies for brain aneurysms. Follow him on twitter at @aminadibi

Part 1 and Part 2 of my summary on CCRM’s Cell and Gene Therapies Workshop (CGTW16) focused on cell manufacturing best practices, scale-up challenges, and closed systems. In this final post, I will share learning points on how to run a successful clinical study, think about cost-effectiveness, and approach regulators.

Dr. Terrence Yau, Director of Research in Cardiovascular Surgery at Toronto General Hospital, was the first speaker to share his insights on designing and conducting cell therapy clinical trials. According to Dr. Yau, when it comes to a new cell product, the top three issues for research ethics boards, Health Canada and the FDA are, “safety, safety and safety!” Towards that, one must develop standardized and reproducible cell preparation processes. “You need to have standard operating procedures for everything, including how to write standard operating procedures,” he says. He also talked about safety and efficacy endpoints. Long-term fate of cells, and their potential to cause a tumour or arrhythmia, are main safety concerns, whereas cardiac function and perfusion, as well as changes in electrical and/or physical function of the heart, are the focus of efficacy evaluations in cardiac studies.

A major challenge in cardiac cell therapy is patient enrollment and the trade-off between recruitment criteria and homogeneity of the study population on one side, and generalizability of results on the other. As Dr. Yau explained, “patients need to be sick enough to justify their entry into phase I/II trials, but not so sick that the safety profile is compromised.”

Another reason for narrow patient enrollment is to make the population more homogenous. That makes it easier to evaluate the effect of cell therapy, as it is unclear how the mechanism of action would interact with other comorbidities. On the other hand, narrow patient enrollment makes it harder to generalize the results. It all comes down to a trade-off. One interesting anecdote Dr. Yau shared was that, “in cardiology, 20 million mesenchymal stromal cells (MSCs) have shown effectiveness, while 200 million MSCs have shown no effect; dose-response is not a given,” says Dr. Yau.

Dr. Sowmya Viswanathan, Associate Director of Cell Therapy Program at University Health Network and principal investigator on the first Canadian autologous MSC trial for osteoarthritis, opened her talk by reviewing the history of the bone marrow transplantation – the most successful cell therapy of all time.

The first report of allogeneic (donor) bone marrow transplant in humans was published in 1957 by Don Thomas. However, the trial was a complete failure; not a single patient survived beyond 100 days. Subsequent preclinical work by Thomas and his colleagues revealed the importance of leukocyte antigen matching in donor selection and led to trials in matched siblings a decade later, which showed very limited success. In 1975, Thomas reported a successful cure for a minority of patients.

As Dr. Viswanathan explained, further improvements in patient care and preparative regiments led to cure rates above 50% for unrelated matched donor/recipient transplants. It also led to the subsequent formation, in 1974, of the UK-based Anthony Nolan, the world’s first marrow registry, and the U.S. National Marrow Donor Program, in 1986. Dr. Thomas was subsequently awarded the Nobel Prize in Physiology or Medicine in 1990, jointly with Dr. Joseph Murray, for “their discoveries concerning organ and cell transplantation.”

Today, many bone marrow registries operate across the globe with more than 28 million registered donors, and 50,000 bone marrow transplants being performed routinely every year. “It didn’t start out as a success. In fact, people were dying in these clinical trials,” says Dr. Viswanathan of bone marrow transplantation. It was the iterative process of going from the bench to the bedside and back to the bench, she argues, that made it the standard-of-care it is today. “People went back to the bench, refigured things, reconfigured, put together crucial pieces of information that was missing, and then went back again to the clinic,” according to Dr. Viswanathan.

She also emphasized the need to engage with regulators early on in order to take a reasonable approach towards addressing safety and efficacy issues, a sentiment shared and echoed by many other experts in the room, including Dr. Michael Rosu-Myles, the Manager of Regulatory Research in the Division of Health Canada’s Biologics and Genetic Therapies Directorate. Dr. Rosu-Myles further underscored that supporting cell and gene therapy innovations is a priority for Health Canada, citing that Health Canada has so far issued 58 No Objection Letters for cell and gene therapy clinical trials, held 40 pre-submission meetings and authorized one cell therapy product.

L-R Aaron Dulgar-Tulloch, Nick Timmins, Greg Russotti, Kim Warren

L-R Aaron Dulgar-Tulloch, Nick Timmins, Greg Russotti, Kim Warren

I asked the panel of experts from CCRM, GE Healthcare, Celgene and AvroBio whether they thought FDA and Health Canada regulations were slowing down development of cell and gene therapy products. I was interested in hearing their thoughts, especially in light of recent controversies around the REGROW Act in the U.S. (see here, here and here). It was encouraging to hear that the entire panel was unanimous in their support of the role of regulatory agencies. “Regulators help us, they are not impeding progress,” says Dr. Greg Russotti. It only takes a month to get a green light from regulators for a trial; “in comparison,” he added, “putting contracts in place takes much longer.” It was also mentioned that the biggest challenge for developing a cell therapy product in Canada is an entrepreneurial one, not regulatory. Capital is what is lacking.

The final expert to share his insights was Dr. Chris McCabe, health economist and principal investigator on Genome Canada’s PACEOMICS project. Dr. McCabe talked about cost-effectiveness of cell and gene therapies, an important issue that is sometimes overlooked in academic settings. Since healthcare budgets are constrained, “it is ethical to think of therapies in cost-effectiveness terms. It’s not money, it’s someone else’s healthcare,” he said. He underscored that it is important to think about product development in a Value-Engineered Translation framework, so that the end-product aligns with the needs of our health system. One can use this approach to establish the minimum commercially sustainable price, which in turn will inform developmental and translational decisions and establish the magnitude of effect required to support a positive reimbursement and/or coverage decision. In Dr. McCabe’s words, “a paid invoice is a treated patient.”

As you can probably tell, I had a very productive time at this year’s workshop and learned a lot. I hope those who were not able to attend will find my three summaries useful.


The following two tabs change content below.


Signals Blog accepts guest blog posts on topics relevant to stem cells and regenerative medicine, as well as submissions for its Right Turn Friday feature. See for more information.
Tags: , , , , , , , , , , , , , , , ,

Leave a Reply