ACT To Sustain: Adoptive Cell Therapy To Sustain access to non-commercialized genetically modified cell therapies

Abstract

Genetically modified cell therapies (GMCT), particularly immune effector cells (IEC) such as chimeric receptor antigen (CAR) T cells, have shown promise in curing cancer and rare diseases after a single treatment course. Following close behind CAR T approvals are GMCT based on hematopoietic stem cells, such as products developed for hemoglobinopathies and other disorders. Academically sponsored GMCT products, often developed in academic centers without industry involvement, face challenges in sustaining access after completion of early phase studies when there is no commercial partner invested in completing registration trials for marketing applications. The American Society for Transplantation and Cellular Therapy (ASTCT) formed a task force named ACT To Sustain (Adoptive Cell Therapy to Sustain) to address the “valley of death” of academic GMCT products. This paper presents the task force’s findings and considerations regarding financial sustainability of academically sponsored GMCT products in the absence of commercial development. We outline case scenarios illustrating barriers to maintaining access to promising GMCT developed by academic centers. The paper also delves into the current state of GMCT development, commercialization, and reimbursement, citing examples of abandoned products, cost estimates associated with GMCT manufacturing and real-world use of cost recovery. We propose potential solutions to address the financial, regulatory, and logistical challenges associated with sustaining access to academically sponsored GMCT products and to ensure that products with promising results do not languish in a “valley of death” due to financial or implementational barriers. The suggestions include aligning US Food and Drug Administration (FDA) designations with benefit coverage, allowing for cost recovery of certain products as a covered benefit, and engaging with regulators and policy makers to discuss alternative pathways for academic centers to provide access. We stress the importance of sustainable access to GMCT and call for collaborative efforts to develop regulatory pathways that support access to academically sponsored GMCT products.

Introduction:

Genetically modified cell therapies (GMCT) can cure cancer and rare diseases after a single treatment course. Immune effector cells (IEC) such as chimeric receptor antigen (CAR) T cells represent a new paradigm in cancer care whereby a single infusion of CAR T cells can lead to durable remissions in patients with multiply relapsed B-cell hematologic malignancies.^1–7 This approach has enormous potential to deliver life-saving therapies to adults and children and perhaps to change the cancer treatment paradigm with a single infusion of engineered cells. Since August 2017, there have been 10 FDA approvals of 6 different IEC products.⁸ Notably only one of these approvals is licensed for pediatric use.¹ Likewise, a single infusion of genetically engineered hematopoietic stem cells (HSC) can potentially cure inherited monogenic diseases such as hemoglobinopathies or immunodeficiencies.^9–12 In 2022, the FDA approved two HSC-GMCTs for the treatment of beta thalassemia and adrenoleukodystrophy, and in December of 2023, two more HSC-GMCTs were approved for treatment of sickle cell disease (SCD).

Most of the currently approved GMCT products were initially developed by academic centers and subsequently licensed to the pharmaceutical industry (Table 1), combining the strengths of academia (innovation, focus) with those of industry (infrastructure, resources, and the expertise to support registration trials for commercialization). Academic institutions are highly effective in conducting early-phase, innovative, rapidly iterating, high quality clinical trials that simultaneously test biologic hypotheses and offer life-saving treatment while following the most stringent regulatory practices.

Table 1.

Approved GMCT path to clinic

Commercial Product	Disease Indication	Early phase clinical trials	Pivotal Registration Trial	Commercial Manufacturer
Tisagenlecluecel	B-ALL, DLBCL	UPenn/CHOP (NCT01626495, NCT01029366)	Novartis (NCT02445248; NCT02435849)	Novartis
Axicabtagene ciloleucel	B-NHL	NCI (NCT00924326; NCT01593696)	Kite Pharma (NCT02348216, NCT03391466)	Gilead
Lisocabtagene maraleucel	B-NHL	Seattle Children’s (NCT02028455); Fred Hutchinson Cancer Center (NCT01865617)	Juno Therapeutics (NCT02631044)	BMS
Brexucabtagene autoleucel	Mantle Cell Lymphoma, B-ALL	NCI (NCT00924326; NCT01593696)	Kite Pharma (NCT02614066)	Gilead
Idecabtagene vicleucel	MM	bluebird bio (NCT02658929)	Celgene Corporation (NCT03361748)	BMS
Ciltacabtagene autoleucel	MM	Legend Biotech (NCT03090659)	Janssen Biotech (NCT03548207)	Janssen Biotech
Exagamglogene autotemcel	Sickle Cell		CRISPR Therapeutics and Vertex Pharmaceuticals (NCT03745287)	Vertex Pharmaceuticals
Lovotibeglogene autotemcel	Sickle cell		bluebird bio (NCT02140554)	bluebird bio
Betibeglogene autotemcel	Beta thalassemia	bluebird bio (NCT01745120, NCT02151526)	bluebird bio (NCT02906202)	bluebird bio
Elivaldogene autotemcel	Active cerebral adrenoleukodystrophy	Hopital Saint-Vincent de Paul, Paris France (Cartier, N et al, Science 2009)	bluebird bio (NCT03852498; NCT01896102)	bluebird bio

B-ALL B cell acute lymphoblastic leukemia; DLBCL diffuse large B cell lymphoma, B-NHL B cell non-Hodgkin lymphoma; UPenn University of Pennsylvania; CHOP Children’s Hosptial of Philadelphia; NCI National Cancer Institute; MM multiple myeloma; BMS Bristol Myers Squibb

In drug development, the term “valley of death” is used to describe the large gap between basic scientific research and clinical testing of novel therapies.¹³ Increasingly, it appears that GMCTs that clear this first translational hurdle with a successful proof-of-concept trial fall prey to a second implementational valley of death––one in which an academic trial with a clear efficacy and safety signal may not be followed up by registration studies due to lack of commercial interest and financial support by pharmaceutical partners (Figure 1).

Figure 1:

The interaction of academic and biopharma clinical development paradigm for new genetically modified cell therapies. Preclinical testing in an academic setting can yield a research IND used by the academic sponsor in early phase clinical trials to show proof of concept and early evidence of tolerability and efficacy. There is the potential for intellectual property (IP) from the academic sponsor to be licensed to a biopharma partner for commercialization at several points during development. The biopharma partner then submits a commercial IND for further clinical development which may ultimately lead to a commercial product if a successful BLA submission is granted FDA approval. However, in the absence of a biopharma partner, or at any time if the partner makes a decision to cease development and abandon the IP, products are shelved in what is termed the valley of death. In academia, there is often iterative development of successive GMCT based on the development of new technology combined with early data from clinical trials of an early generation GMCT which may also lead to a valley of death for promising products, limiting access to small numbers of participants in a clinical trial.

This gap leaves certain patient populations (e.g. children, those outside large academic centers) and/or disease subsets (e.g., very rare diseases) that would be considered highly likely to benefit from these therapies without access to them. Lisocabtagene maraleucel was developed at Seattle Children’s Hospital with early phase trials conducted in pediatric B-ALL.¹⁴ Commercialization of this product for use in children with B-ALL was halted by Bristol Myers Squibb (BMS) in 2023, leading the academic institution to spin out and fund Brainchild Bio, a biotech whose sole purpose is to ensure that CAR T cells designed for children are advanced to clinical use in children. A highly effective gene therapy was developed at the University of California Los Angeles (UCLA) for Severe Combined Immune Deficiency characterized by mutations in the adenosine deaminase gene (ADA SCID).¹¹ This product was licensed to Orchard Therapeutics, which ultimately decided not to pursue the therapy and returned the rights to the intellectual property to UCLA.¹⁵ Other recent biopharma departures from the hemoglobinopathy field for business reasons include those of Sangamo and Novartis. Particularly noteworthy is the decision of bluebird bio to withdraw its thalassemia gene therapy from Europe despite obtaining marketing approval, in part due to pricing restrictions.¹⁶ Although specific data detailing the cost of bringing a GMCT to market is scant/scarce, one study estimated the cost of bringing a GMCT to market as $1.94 billion (95% confidence interval $1.395 – 2.49 billion).¹⁷ Given the small target populations of patients for whom a given therapy may be appropriate, it is not surprising that traditional pharmaceutical companies may not find GMCT products for rare indications a financially viable proposition.

In Europe, the hospital exemption (HE) pathway allows patient access to advanced therapeutic medicinal products (ATMPs) that are prepared according to quality standards on a non-routine (e.g. custom or personalized) basis.¹⁸ The HE path to clinical development allowed a single academic center (Hospital Clinic, Barcelona) to be the license holder for an autologous CART-19 product for use in adults and children after the initial proof of concept clinical trial.^19,20 This product, named ARI-0001, received authorization from the Spanish Agency of Medicines and Medical Devices (AEMPS) for administration of the investigational product and financial reimbursement. This occurred under the HE approval pathway in February 2021 for the treatment of patients aged > 25 years with relapsed/refractory B-ALL.²¹ Reimbursement negotiations with the Spanish Ministry of Health were inclusive of the cost to manufacture and distribute the product as well as to support the administration of regulatory documents and compliance. Notably, the HE only allows for a product to be administered within the same jurisdiction (EU state) where it was developed to comply with national pharmacovigilance requirements. ²²

To raise the issue of academic GMCTs that enter the valley of death and determine how to best address it, the American Society for Transplantion and Cellular Therapy (ASTCT) formed a task force entitled ACT To Sustain (Adoptive Cell Therapy to Sustain). The specific goals of the task force include: 1) to evaluate the current regulatory framework in the US for providing access to GMCT; (2) to describe the financial burden on academic sponsors; 3) to bring awareness to the mechanism of cost recovery and inquire when and how the process has been used to date; and 4) expand knowledge of federal coverage and payment policies for GMCT products (including from Centers for Medicare & Medicaid Services; CMS) and specifically how reimbursement of cell therapy products that are not commercially licensed might be achieved. In this paper, the task force presents their findings and considerations around these issues with a focus on how to sustain an academically sponsored GMCT product in the absence of plans for commercial development.

Case Scenarios

The following case scenarios illustrate the barriers to maintaining access to promising GMCT that are developed in academic institutions and do not have a clear pathway to commercialization. Each case underscores the urgent need to make academically-sponsored GMCT available beyond the initial early phase clinical trials once there is evidence for safety and efficacy. The key barrier to sustainable access is monetary as dedicated funds are required to cover the cost of manufacturing, maintenance of the regulatory documents, and infrastructure to support the ongoing use of the investigational product.

Case#1: CAR product with demonstrated safety and efficacy; no commercial partner

An 8-year-old with B-ALL has recurrent, chemo-refractory disease with marrow and central nervous system (CNS) involvement following treatment with commercial tisagenlecleucel. Leukemic blasts are now CD19 negative but retain expression of CD22. While inotuzumab ozogamicin could be an option, this agent lacks activity in the CNS. The treating team therefore feels that the best option would be treatment with a CD22 targeting CAR T cell therapy which has demonstrated the ability to penetrate and exert antitumor activity in the CNS and bone marrow. The CD22 CAR T cell therapy developed by NCI demonstrated a tolerable safety profile with encouraging efficacy, particularly in patients who had already received a CD19 targeting therapy with resultant antigen escape.²³ As of September 2023, there is still not a commercially available option and there are no industry-sponsored studies of autologous CD22 CAR T cells for pediatric ALL patients.

Case#2: Commercially available CAR product is available but clinical setting is considered off-label

A 21-year-old with 1^st relapse of B-ALL needs a CD19 CAR T cell therapy. The insurance company denied prior authorization for a commercial product as he did not meet the definition of refractory disease or 2^nd relapse. Furthermore, although there have been large efforts by the pediatric oncology consortiums to advance autologous CD19 CAR T cell therapy in 1^st relapse B-ALL, there are no industry sponsored trials available. Due to historic chemotherapy related complications with chemotherapy, the treating physician is hesitant to proceed with alternative salvage chemotherapy. An institutional trial of an academic-sponsored CD19 CAR T cell therapy recently completed accrual and phase 2 data demonstrated efficacy and tolerability in 1^st relapse B-ALL.

Case#3: Engineered hematopoietic cell transplant for a rare disease that is not available commercially despite promising clinical results.

A 3-month-old boy was diagnosed with severe combined immunodeficiency due to adenosine deaminase deficiency (ADA-SCID) on newborn screening. He is receiving enzyme replacement therapy with pegylated ADA and has no available matched transplant donors. The family has learned of successful clinical trial results using a lentiviral vector mediated gene addition HSC product but were disappointed to find out that the biotech company developing the product had abandoned the pursuit of this product. The original academic center where the project originated now holds the IND for this obstensibly highly effective treatment but has limited funds and can only support the treatment of 12 additional patients as part of an expanded access program at UCLA.

Current state of GMCT development, commercialization, and reimbursement

Possible solutions to the problems illustrated in the above case studies must be considered in view of the current regulatory and legal environment, logistic and other resources, and financial implications. In each of the above cases, our proposed “ideal” solution would be for the academic center to obtain reimbursement for the GMCT from a third-party payer to cover the costs of manufacturing the product and maintaining an expanded access protocol.

GMCT trials in academic institutions

Academic centers have positioned themselves as the prime movers in the current landscape of GMCT trials. Since GMCT are largely personalized products, academic centers play a key role in identifying and recruiting participants for GMCT research and arguably are best positioned to develop and manufacture products in their GMP facilities. Unlike the earlier paradigm of drug development wherein largely preclinical research and development took place in academic labs, currently both GMP manufacture and initial proof of concept clinical trials can take place in academic institutions without necessitating involvment of the biopharmaceutical industry. This process can often extend to efficacy evaluation as part of a phase 2 trial before transferring development to an industry partner, which de-risks clinical aspects of the drug development process.

This work may be financially sponsored by an industry partner, allowing the academic medical center to limit the extent of their investment in the early clinical development of the new product. However, often the academic sponsor relies on a mixture of philanthropic, institutional, and grant funding to develop new GMCT products. A search of clinicalTrials.gov on January 8, 2024, using the term CAR and filtered on “recruiting”, “investigational”, “United States”, “early phase 1”, “phase 1”, and “phase 2” resulted in 280 trials. Of these, there were 197 that appeared to have a primary intervention of a novel CAR product. An academic medical center or principal investigator was listed as the sponsor of 113 (57%) of these trials, of which only 22 (19% of the academic medical sponsored trials) indicated at least a portion of the funding was provided from industry. These results are consistent with the majority of novel CAR T cell products being developed in academic institutions without biopharma involvement.

Regulatory Pathways for approval of a GMCT product

The traditional pathway of drug development is currently in use for approval of GMCT. After completion of early phase trials with positive safety and efficacy signals, it is expected that a registration trial will occur, followed by submission of a biologic license application (BLA) to the FDA’s Center for Biologics Evaluation and Research (CBER). If approved, the product would then be labeled for commercial sale. It is highly unlikely that academic institutions will conduct pivotal trials with registration quality data and submit a BLA for commercial approval as they lack the finances and expansive infrastructure required for such a task. Even if an academic sponsor could successfully submit and obtain approval of a BLA, they do not have the manufacturing and commercial apparatus by which to provide broad access, and one could argue that an academic sponsor would have a significant financial conflict of interest if they were to become a commercial provider of the GMCTs they use to treat patients.

The orphan drug designation is an example of an incentive for companies to pursue approval in rare diseases, in situations where it may not be profitable to produce a medical product for a small patient population without government or other assistance. Practical implications of this in the US include reduced barriers to marketing approval or other financial incentives such as an extended period of exclusivity, tax credits for qualified clinical trials and exemption from user fees. Despite these incentives, we continue to see abandoned GMCTs due to financial projections not providing a sufficient return on investment.

Process of Cost Recovery

In the absence of commercialization, one possibility that has been discussed is keeping a research IND open, providing access to the GMCT through an expanded access program, and seeking approval to charge the cost of production of the investigational agent to a payer. The Code of Federal Regulations (CFR) Title 21 Part 312, subpart A section 312.8 contains provisions for seeking reimbursement for investigational drugs administered under an IND (generally referred to as “cost recovery”). The specifics of the CFR allow a sponsor to charge for the investigational agent in the context of a clinical trial or expanded access program if certain criteria are met. The sponsor must obtain prior written authorization from the FDA to charge. When reviewing a cost recovery request, the FDA considers the following criteria: evidence that the drug has a potential clinical benefit, and that through further investigation, it may be found to be more advantageous than alternative available treatments; the data from the clinical trial are essential to establish the drug is effective and safe;and that the trial could not be conducted without defraying the cost of the drug, which would be extraordinary to the sponsor. For expanded access, the treatment must not interfere with the development of the drug for marketing approval. This includes demonstrating sufficient enrollment in any ongoing clinical trial needed for market approval, evidence of adequate progress in the development of the drug for marketing approval, and information submitted under the general investigational plan to specify the milestones of the sponsor plan to be met in the next year. When authorization is given for investigational products as part of an expanded access program, the authorization is only active for one year and continued use requires approval sought from the FDA on an annual basis.

The CFR also specifies what is considered an allowable charge in the calculation for the price of a product’s production. Only the direct costs of making the product are allowable – which include the raw materials, labor and non-reusable supplies and equipment used to manufacture as well as costs associated with shipment and storage. Indirect costs such as research and development, administrative costs to submit documents to regulatory authorities, biomarker development, or other costs that would occur even if the clinical trial or treatment did not occur may not be included. It is worth noting that the term “indirect costs” as used in this context differs from the use of “indirect costs” as used by funding agencies. One exception to allowable costs is when cost recovery is obtained in the context of expanded access. In these cases, the cost may also include the costs of monitoring the expanded access protocol/IND, complying with IND reporting requirements and other administrative costs directly associated with the expanded access IND.

The application from the sponsor to the FDA must document that the calculation of cost is consistent with the requirements and was reviewed by an independent certified public account (CPA) who has approved the calculations. Costs associated with major categories such as raw materials, equipment, personnel, shipping, and storage should be included. The sponsor must explain why the clinical trial or expanded access could not be done without cost recovery. In August of 2022, the FDA released a draft guidance entitled “Charging for Investigational Drugs Under an IND Questions and Answers Guidance for Industry” which was finalized in February 2024.²⁴ This provides further clarification around the submission process, the role of the CPA, and the inclusion of regulatory costs with expanded access IND cost recovery. This guidance also notes that although not required, it is the FDA’s intention to answer cost recovery submissions within 30 days of receipt.

Coverage and reimbursement for investigational products

The FDA does not decide or have authority over how reimbursement is obtained once permission to charge for cost recovery is granted.²⁵ Nor does the FDA have authority over CMS or any third-party payer reimbursement policies or decisions for investigational drugs. It does serve as a starting point for discussion with the payers regarding a specific approval that allows for reimbursement.

Affirmative policies from insurance companies that allow for coverage of investigational agents are very rare, and typically health insurance policies contain language that specifically excludes such coverage. Policies that have language around coverage of clinical trials frequently include specific information defining what is covered as it relates to routine costs. An investigational product is not considered a routine cost related to participation in a clinical trial and is excluded as a covered benefit. On occasion, payers may make exceptions and provide coverage of experimental procedures or agents for life-threatening conditions. Often the policies related to these exceptions are imprecise, and it is unclear what the insurance company is and is not likely to cover. Critically, private payers may refuse payment due to lack of FDA approval and/or formal approvement of payment policies by CMS, creating a “chicken and egg” situation wherein patients are refused coverage even if no commercial alternatives exist, even with encouraging efficacy of such therapies in Phase 1 and 2 trials.

Institutional survey of cost of manufacturing and use of cost recovery mechanism

As part of our task force activities, we sought to understand the current costs of manufacturing and to what extent institutions attempted to utilize the mechanism of cost recovery. A recent analysis by the Institute for Clinical and Economic Review suggest that the average cost of a commercially available cell therapy is around $1M, but when considering just the cost of goods sold, estimates of autologous cell therapies are in the range of $100,000-$300,000 per dose.²⁶ In an anonymous survey, we collected information from six large centers with academic GMP manufacturing capabilities, of whom five were able to provide cost estimates of manufacturing IEC products. The costs ranged from $57,000 – $90,000, inclusive of costs of the direct materials and labor as well the costs associated with release testing, but not facility costs. Only two institutions included the institutional indirect or overhead costs and, similarly, only two included the cost of the vector, suggesting that the true all-inclusive cost of an academic IEC product is in the range of the marginal cost estimates provided above regarding commercial IEC therapies.

An additional identifiable survey was sent to 26 targeted institutions who were known to have academically sponsored IEC trials with GMP facilities on site for manufacturing. Responses were received from 13 institutions and although all 13 cited familiarity with cost recovery for investigational products, only five knew how to apply. Six of the respondents’ institutions had applied previously for cost recovery with at least one investigational product, and of those products, 3 were associated with phase 1 trials, 3 with phase 2 trials, and 2 with expanded access treatment. Five responded that they had applied for cost recovery with an IEC product; however only 3 were for an IEC product and two were associated with hematopoietic cell transplantation.

For the costs included with the cost recovery price estimate, five included all the costs of the raw materials; one did not. Associated labor costs were included for all six, with three also including storage/shipping costs; two did not and one was unsure. For the two applications associated with an expanded access treatment, neither included the regulatory costs of maintaining the expanded access program. Respondents estimated that cost recovery fees authorized by the FDA covered 40–60% of the true costs.

Cost recovery reimbursement data was largely unavailable. There was at least one institution who reported receiving reimbursement from a Medicaid payer, Medicare, and private insurers. However, no detailed information was available as to the rate and frequency of reimbursement. Thus, it is likely safe to assume that inadequate coverage policies equate to inadequate reimbursement.

Potential solutions to improve access and ensure that products with promising results do not languish in an implementational “valley of death”.

If provision of investigational GMCT through expanded access protocols with cost recovery is to be used as a means to sustain access to academic products that have not been commercialized, several barriers would need to be resolved and/or clarified. First, the price of the GMCT product that is authorized by the FDA for use would need to reflect the true costs. Per current FDA guidelines and the Code of Federal Regulations, permission to charge should grant authority to charge for true production costs. Discussions may be needed between academic centers and the FDA to ensure that when an institution applies for cost recovery with a given product, they receive guidance regarding critical and supporting information that should be submitted to enable recovery of the true costs of delivering the product to patients.

Second, there needs to be alignment among all payers, both government and commercial, that there is value to covered members receiving these therapies and associated impetus for payers to modify coverage policies to allow for reimbursement of a subset of products that have received authorization for cost recovery though not marketing application. It should be noted that we are not advocating for all investigational GMCT to be eligible for coverage and reimbursement. Rather, trial sponsors would need to provide clinical evidence that the products under investigation meet basic safety and efficacy requirements. Coverage policies would need to be updated to support a utilization management review for a service request of this type. One suggestion may be to provide coverage of investigational products when given in the expanded access setting – i.e. when completion of clinical trial data has already occurred and access to such an investigational therapy provides potential benefit or access that approved therapies cannot offer.

It is helpful to understand the categorizations of investigational devices as an example of how reimbursement for investigational GMCTs could occur with alignment between the FDA and CMS. In 1995, the FDA and CMS entered an interagency agreement to codify a specific subset of investigational devices for which the FDA would categorize and CMS could create coverage policies for.²⁷ This was later modified in a 2013 final rule amendment published by CMS and codified in 42 CRF 405.211. Categorization of IDEs is conducted by the FDA and codified in the 42 CFR 405.201. Devices are granted Category B designation when they meet the following criteria: are considered non-experimental/investigational after the underlying questions of safety and effectiveness are resolved; the device type is known to be safe and effective because other manufacturers have obtained FDA approval for that device type; and the device is under investigation to demonstrate substantial equivalence to a predicate device. Devices not meeting these criteria are considered experimental/investigational and are assigned a category A designation by the FDA. Cost recovery is authorized by the FDA for category B IDEs and CMS will consider coverage of devices categorized as such. Ultimately this interagency work between FDA and CMS allows for recovery of costs through alignment of benefit coverage with FDA designations.

As a task force, we believe it would be beneficial for the FDA and CMS to consider categorizing and covering research INDs, as they do for IDEs. Categorization of INDs would enable CMS to create coverage policies that allow for cost recovery of products when appropriate (Figure 2). We would expect that the FDA would review available data regarding safety and efficacy from a given novel GMCT clinical trial and subsequently designate research INDs as category B if the data was consistent with initial demonstration of safety and efficacy. Ideally, the data required by FDA to make this determination would be less onerous than what is required for a BLA as the use of the GMCT would still be under an IND. This would then be attainable for an academic institution to complete with current resourcing. Using the interagency agreement of 1995 as precedent, CMS could draft policy coverage for investigational agents administered through an expanded access protocol on a category B research IND as a covered benefit, similar to the coverage for category B IDEs. While CMS policies do not dictate those of commercial payers, modifications of this type may lead to more productive discussions about cost recovery with those entities as well. Lastly, because this is for proposed only for research INDs, this should not impede any commercialization plans.

Figure 2.

Proposed new pathway for cost recovery to be aligned for research INDs, for potential financial sustainability. In the current state, there is no connection between FDA authorizing cost recovery and coverage policies allowing for reimbursement of investigational products. A proposed solution to this could be the creation of a specific designation to research INDs. If early clinical trial data demonstrates promising efficacy and tolerability, a review could occur by the FDA. In the ideal state, the amount of data required by FDA would be less onerous than what is required for a BLA submission. Once granted category B designation with FDA authorized cost recovery, the goal would be to work with payers to include specific language in their policies to allow for reimbursement of category B IND products, modeled after the investigation device development and precedent of CMS payment for category B IDE devices.

Conclusion

As the field of cell and gene therapy rapidly evolves and more and more diseases become amenable to treatment with novel cellular products, steps will need to be taken to allow broad access to this class of therapeutics. This includes rare, orphan, and ultra-rare disorders. Additionally, there is an abundance of academic GMCT products unlikely to be commercially viable in the current pharmaceutical industry; we need to work now to ensure that we avoid the valley of death for these potentially impactful therapies.

Our task force assessed the existing regulations and use of cost recovery. It is apparent that in its current state, it is unlikely to yield the sustainable solutions we seek for our patients. Precedents from the investigational device arena provides hope for creating policies and modifications to the CFR which could yield a path to financial coverage of investigational GMCTs. This path may be particularly beneficial in a rapidly evolving field of therapeutics where the “best” current product may quickly become outdated, wherein biopharma may be unwilling to risk the upfront investment required to take a product through full BLA and commercialization. Without the full investment required for a BLA, sponsors could then invest in the iterative development of increasingly novel therapies, while sustaining access to already developed therapies. This iterative approach is a key component of academic innovation, as GMP manufacturing does not have to be “frozen” in a specific process, as is necessary prior to a BLA submission.

An additional challenge is that life-saving GMCT products are at present only available at select academic medical centers, limiting broader access. Although it could be considered a success if institutions are able to recoup the full manufacturing costs of a product administered to a patient, we should strive for access available broadly in the US and beyond. Ultimately, we hope that academic manufacturers are able to distribute manufactured products and recover costs from the centers where product is shipped for infusion. These same centers that provide commercially approved GMCTs would then also be able to access these non-commercially viable GMCT products. Although we do not believe that optimal cost recovery regulations will be the end solution or should replace the intent or hope to achieve commercialization, this pathway would address many issues encountered for a subset of criticial GMCTs otherwise destined for the valley of death.

We are excited that other groups in cell therapy and adjacent fields are beginning efforts to address these issues, which we expect to occur increasingly more frequently as more indications arise for curative cell and gene therapies. Academically developed viral specific cellular therapies and gene therapies have also been known to have similar challenges, therefore we anticipate this paradigm could also be applicable outside of GMCT. This is not just a US-based problem but an international issue. In Europe, the AGORA consortium was formed to tackle issues related to ultra-rare disease such as genetic immunodeficiencies and errors of metabolism, to explore the hurdles that currently exist, and identify potential changes and actions to allow for sustainable access to treatments.²⁸ The vision of AGORA is to create an independent not-for-profit entity to support marketing authorization, delivery and access to therapies which are not commercially sustainable in the current industry space. In the US, the Innovative Genomics Institute put together a task force of 30 international experts and produced a 75-page report to bring awareness to the issues surrounding the ability to make genetic therapies affordable and accessible, in order to start conversations and promote change to the field.²⁹ This task force’s vision is similar to that put by AGORA, prosposing that a new type of industry needs to be born in order to support the commercialization of cell and gene therapies for rare indications.

The example of Hospital Clinic, Barcelona providing a CD19 CAR T cell product to patients is encouraging but the success of this strategy was in part predicated on the ability to negotiate the coverage and reimbursement within a single payer system. Even within Europe, there is heterogeneity regarding interpretation and implementation of the HE rules, due to differences in interpretation of criteria that define HE, lack of clarity in national legislation around ATMP, and flexibility of language around ATMP-specific GMP guidelines, thus prohibiting the use of AIR-0001 outside of Spain.²¹ In September 2022, the EMA launched a pilot to support clinical translation of promising ATMPs by academic sponsors and non-profit organizations;³⁰ AIR-0001 was the first product to enter the pilot. During this pilot program the EMA will provide regulatory support for up to 5 selected ATMPs that address unmet clinical needs, including regulatory guidance, planning clinical development, fee reductions and waivers. Notably, the EMA did not undertake or introduce a new regulatory provision or tool, and it is too early to know if this pilot program will be successful, sustained, or expanded.

Depending on their success, these precedents may inform future access pathways for academic GMCT products. We believe academic products can successfully fill gaps within a framework in which not only does the FDA allow for cost recovery by CMS, but also facilitates analogous pathways to third party payer reimbursement which is critical for the financial solvency of most health systems. Moving forward, we hope for a collaborative process and dialogue between regulators, policy makers and payers to develop alternative pathways for academic centers to provide access to increasingly valuable therapies. Ultimately, we believe these efforts will yield novel alternative models for GMCT developed for ultra-rare disease indications that yield increasingly transformative and sustainable therapies for our patients.

Highlights.

• Most new genetically modified cell therapy (GMCT) products in early phase trials are academically sponsored

• Many promising academic GMCT products encounter a “valley of death” due to lack of a commercial partner

• New regulatory pathways are required to create a fiscally sustainable model for access to promising academic GMCT that have a low likelihood of advancing to commercialization