NA LRA Watchdog - August 2023

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Write-up on a Roundtable Session:
“Regulating MSC Clinics: Are we doing enough to protect patients”
at the ISCT 2023 Annual Meeting in Paris

Sowmya Viswanathan, PhD
University Health Network
Canada

The roundtable session on “Regulating MSC Clinics: Are we doing enough to protect patients?” was co-chaired by Sowmya Viswanathan, PhD and Christian Jorgensen, MD, with Bambi Grilley, RPh, CCRC, CCRP, CIP, RAC, Laertis Ikonomou, PhD and Miguel Forte, PhD serving as expert panelists. The session was divided into two parts.

The first part of the roundtable focused on unregulated, direct-to-consumer clinics with a case study on the recent California Federal Court ruling in favor of the defendant’s position, the Cell Surgical Network in Beverly Hills, that stromal vascular fraction (SVF) and culture-expanded autologous adipose-tissue derived mesenchymal stromal cells (MSCs) are not drugs, and, therefore, not under the jurisdiction of the Food and Drug Administration (FDA) [1]. Judge Bernal ruled that the SVF and MSCs were part of the “Same Surgical Procedure Exception” [2] and agreed with the defendants that their manipulation was not greater than that done during routine surgical procedures. The decision is currently being appealed by the FDA.

The panel strongly condemned the judge’s ruling, calling the rationale “sloppy science” and re-iterated the International Society for Cell & Gene Therapy (ISCT)’s position against this ruling [3]. Ikonomou was optimistic that this ruling was not part of a larger trend, would not set a precedent, and likely be reversed upon appeal. Importantly, both ISCT and the International Society of Stem Cell Research (ISSCR) have filed an Amicus brief, which is a legal document supplied to a court of law containing advice or information. Grilley shared this optimism but added that if this optimism was misplaced, it would “wreak havoc in the US; clinical trials would not be able to compete with these clinics.”

Viswanathan clarified that it’s already difficult to do clinical trials due to limited interest from companies. The panelists discussed that sometimes medical device licenses for devices that process cellular products are issued to companies who may not be interested in generating clinical trial data for the processed cellular product in specific indications. Thus, the onus to conduct such trials lies on academic investigators who need to raise significant capital.

Patient confusion, and access to reliable, simple, and straightforward information were discussed next. The technicalities of the arguments in this case surrounding definitions of “minimal manipulation [4]” (which both SVF and culture-expanded MSCs do not meet), and “same surgical procedure exception [2] were thought to be too technical nuanced and therefore difficult to communicate to the lay public. The arguments should be simplified and presented to the public who would understand non-homologous use [5]; “you can’t put fat into your eyeball”. However, it was acknowledged that this would be harder to communicate for musculoskeletal indications, where there is evidence of safety and mixed evidence of efficacy. Improved communication and roles for ISCT with patient advocacy groups, educating physicians, particularly orthopedic surgeons and dermatologists through disease-specific societies was recommended.

The second half of the discussion centered on regulated access to cell and gene therapies (CGTs) in Europe through the Hospital Exemption (HE) pathway [6], and, in the US, through the expanded access pathway (EAP) [7]Particularly, the “Spanish Model” involving the use of clinical trials to demonstrate safety and preliminary efficacy, registries, Good Manufacturing Process (GMP)-compliant production of CGTs, and reporting of adverse events was discussed as a potential temporary “intermediate pathway” between the two extremes: (i) unregulated, direct-to-consumer clinics vs. (ii) obtaining market authorization (MA) after several rounds of clinical trials.

The panel was divided on the use of HE as an alternate mechanism to provide patients with access to MSCs, particularly for musculoskeletal use. On the one side, there were arguments that this could not be a general mechanism and was not a substitute for the collection of clinical trial evidence. On the other side, there was an acknowledgment that with limited industry involvement, it was difficult to finance clinical trials beyond the early phase. Jorgensen also shared that patients are desperate to get treatments that defer surgical options, and HE could provide a regulated mechanism, particularly when used in conjunction with early-phase clinical and quality data.

The panel also dove into the EAP in the US and its increasing use. Grilley noted that the EAP had moved from its original compassionate use designation to enable large-scale programs and that the rationale for this transition could not be understood. An ISCT working group on EAP has been set up and has published on the emerging issues surrounding the growing use of EAP [7]. The panel thought that the use of EAP led to a “collection of data based on numerous assumptions, not a substitute for randomized clinical trial evidence.”

The discussion concluded with a recognition that educating patients and physicians using simple, straightforward messaging without relying on technicalities of definitions would be important. Here, an important role for ISCT as a translational research society was identified. ISCT can and should play a leadership role in liaising with patient advocacy and disease-specific societies to inform their stakeholders of the risks and benefits of unregulated and regulated access to cellular therapies.

Reference(s):

[1] C. for B. E. and Research, “Important Patient and Consumer Information About Regenerative Medicine Therapies,” FDA, Jul. 2021, Accessed: Jun. 07, 2023. [Online]. Available: https://www.fda.gov/vaccines-blood-biologics/consumers-biologics/important-patient-and-consumer-information-about-regenerative-medicine-therapies

[2] “Same Surgical Procedure Exception under 21 CFR 1271.15(b): Questions and Answers Regarding the Scope of the Exception; Guidance for Industry”.

[3] https://www.isctglobal.org/telegrafthub/people/lauren-reville, “ISCT issues response to US federal judge ruling on FDA regulation of cell and gene therapies,” Sep. 12, 2022. https://www.isctglobal.org/telegrafthub/blogs/lauren-reville/2022/09/12/isct-issues-response-to-us-federal-judge-ruling-on (accessed Jun. 07, 2023).

[4] “Regulatory Considerations for Human Cells, Tissues, and Cellular and Tissue-Based Products: Minimal Manipulation and Homologous Use; Guidance for Industry and Food and Drug Administration Staff,”.

[5] “CFR - Code of Federal Regulations Title 21.” https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm?fr=1271.3 (accessed Jun. 07, 2023).

[6] N. Cuende et al., “Patient access to and ethical considerations of the application of the European Union hospital exemption rule for advanced therapy medicinal products,” Cytotherapy, vol. 24, no. 7, pp. 686–690, Jul. 2022, doi: 10.1016/j.jcyt.2022.03.007.

[7] P. J. Zettler, L. Ikonomou, A. D. Levine, L. Turner, B. Grilley, and B. E. Roxland, “An International Society for Cell & Gene Therapy working group short report on the future of expanded access to unapproved cell and gene therapies,” Cytotherapy, vol. 25, no. 7, pp. 712–717, Jul. 2023, doi: 10.1016/j.jcyt.2023.02.004.

Updates and regulatory news

Health Canada

What’s new in Biologics, radiopharmaceuticals and genetic therapies can be found at:

https://www.canada.ca/en/health-canada/services/drugs-health-products/biologics-radio-pharmaceuticals-genetic-therapies/what-new-biologics-radiopharmaceuticals-genetic-therapies-health-canada.html

Information for health product manufacturers and distributors in relation to COVID-19:

https://www.canada.ca/en/health-canada/services/drugs-health-products/covid19-industry.html

Health-related consultations:

https://www.canada.ca/en/services/health/consultations.html

FDA

OTP Town Hall: Cell Therapy Chemistry, Manufacturing, and Controls – June 8, 2023 (Recording is now available)

https://www.fda.gov/news-events/fda-meetings-conferences-and-workshops/otp-town-hall-cell-therapy-chemistry-manufacturing-and-controls-june-2023-06082023

FDA Approves First Gene Therapy for Treatment of Certain Patients with Duchenne Muscular Dystrophy – June 22, 2023