Jacques Galipeau, MD FRCP(C)
ISCT PresidentDon and Marilyn Anderson, Professor in OncologyAssociate Dean for Therapeutics Development University of Wisconsin School of Medicine and Public Health
In 1968, a toddler with Wiscott-Aldrich syndrome – a lethal genetic bone marrow failure disorder – underwent a successful allogeneic bone marrow transplant (BMT) at the University of Wisconsin in Madison with his sister as a bone marrow donor. This BMT precedent shared that same year with the University of Minnesota in Minneapolis was made possible by the development in 1966 of the MLR (mixed lymphocyte reaction) as a means to identify genetically compatible sibling marrow donors and avoid hematopoietic stem cell graft rejection and minimize GvHD. The impact then on the care of hematological malignancies was akin to the current enthusiasm for CAR-T – a true game changer. Bone marrow transplant was very quickly adopted as a medical service addressing a prevalent unmet medical need with cure. There was explosive growth in academic health centers of BMT programs worldwide. There are now more than 8000 allogeneic hematopoietic stem transplants per year performed in USA alone. These are supported by more than 307 FACT and 256 JACIE currently accredited hospital-based cell processing labs located overwhelmingly in not-for-profit academic centers of excellence. A large majority of these hospital-based programs have decades of experience in hematopoietic donor screening, stem cell collection, processing, labelling, banking, and infusion within GMP-like facilities. This involves maintenance of up-to-date SOPs (standard operating procedures), including facilities quality assurance and maintenance of competency of a multidisciplinary staff, including cell processing technologists, coordinators, nursing, pharmacists and specialty physicians within the context of rigorous maintenance of voluntary FACT/JACIE accreditation. Indeed, FACT accreditation is part of the scorecard of US World News ranking of US-based hospitals as a measure of quality. We are talking about an enormous international pool of talent and facilities specifically designed to deploy cell therapies operationally embedded within healthcare systems.
In the USA, BMT is regulated under section 361 of the PHS act since it involves “minimal processing” of cell products intended for homologous use. FDA marketing approval is not required for pricing and reimbursement in US for PHS 361 products, rather, the burden of medical evidence of utility – and quality accreditation - is what drives coverage by private insurance and Medicare/Medicaid. The total cost of parts (cell product processing) and labor (hospitalization and all ancillary clinical services) of an average myeloablative allogeneic BMT in the USA was $289,283 in 2017 for the first 100 days of cumulative care (https://pubmed.ncbi.nlm.nih.gov/29263771/ ). All clinical outcomes, such as survival one-year post BMT are mandatorily reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) which curates a publicly accessible database for all US-based accredited BMT centers. Note be made, not-for-profit US-based academic health centers are not charities but margin-sensitive service operations. The same holds true for academic centers in jurisdictions with government-funded healthcare. On this predicate, BMT was widely adopted by tertiary healthcare enterprises for the triad rationale of outstanding outcomes for prevalent life-threatening clinical indications with otherwise unmet medical needs and a sustainable reimbursement scheme to health centers to cover parts & labor. BMT programs are typically sized to the needs of the catchment areas of respective hospital systems whose operational remit is regional in scope.
In 1995, the era of advanced cell therapy was formally ushered in by the first published phase I clinical trial report from Case Western University Hospital of POC (point-of-care) culture-adapted mesenchymal stromal cells (MSC) in the setting of an autologous marrow transplant. Distinct from hematopoietic stem transplant, MSCs require extensive ex-vivo culture and handling rendering them a PHS 351 “more-than-minimally-manipulated” and hence regulated as a “drug” by FDA CBER. MSCs, TILs, CARs and the like are all regulated by PHS 351 and require an IND (investigational new drug) license from FDA to conduct clinical trials and further require eventual FDA MA (marketing approval) to be eligible for pricing and potential reimbursement by private and public payors – a pathway to commercialization shared by all pharmaceuticals including pills and biologics.
The prevalent means of achieving MA for PHS 351-regulated advanced cell therapy - and the equivalent EMA (European medicine agency)-regulated ATMPs (Advance Therapy Medicinal Products) is to hand off proof-of-concept achieved in early phase clinical trials by academic centers and transfer technology and scale out to privately owned industrial entities, typically with central manufacturing capacity with a hub and spoke distribution model. This model has allowed for the successful commercial development of a number of useful advanced cell pharmaceuticals, including most notably CAR-T.
The COVID pandemic has taught us the vulnerability of complex vein-to-vein manufacturing schemes involving supply chains, and shipping logistics, to name a few, as well as the pinch point of manufacturing capacity to meet clinical demand of more prevalent cell therapy cases, uses in hematological malignancies. With cell therapies in development for expanded use in oncology, regenerative medicine, and immune disorders, especially where the product is autologous, manufacturing and logistics bottlenecks in the hub and spoke distributive model will face serious headwinds.
Here is where opportunity presents itself for convergence of untapped academic center of excellence PHS-351 manufacturing capacity and commercial deployment at scale of advanced cell therapies – especially autologous or directed allogeneic cell products. The Japanese FDA has indeed seized upon this opportunity by enabling early conditional marketing approval of advanced cell therapies that are manufactured in part by select academic centers of excellence. With the exception of public cord blood banking, there is no precedent for FDA BLA (biologic license application) issued to non-profit academic health centers. That said, both the FDA is now leading discussions in novel regulatory approval pathways that would be better aligned with smaller scaled deployment of advanced cell therapies supported regionally by academic centers of excellence meeting the needs of their patient catchment (https://www.fda.gov/news-events/fda-voices/fda-seeks-feedback-distributed-and-point-care-drug-manufacturing). Indeed, the FDA is engaging in public discourse along these lines and in Europe, the EMA is spearheading a similar initiative to leverage the Spanish network of hospital-based manufacturing competency to deploy ATMPs (Cell and gene therapies from academia: EMA to help 5 projects going after unmet clinical needs).
The ISCT is a natural gathering place for this conversation to move forward especially considering our partnership with FACT, JACIE and sister organizations historically invested in clinical stem cell processing, development, and deployment. Here exists the unique opportunity to innovate with our diverse membership in defining novel, margin friendly and sustainable regulatory and commercial development schemes that leverage the enormous, decentralized point-of-care vein-to-vein (POCV2V) GMP and service line competencies held by hundreds of accredited academic health centers of excellence worldwide.
Now more than 50 years after the first cure of a gravely ill child with cell therapy and buoyed by the step-change of advanced cell therapy exemplified by CAR-T technologies, we are poised to go to the next step of ensuring accessible and sustainable, margin-friendly deployment of cell cures, both scaled up within industrial facilities complemented by scaled out distributive model enabled by a worldwide network of locally sourced healthcare centers of excellence.