Pathing the way from regulatory approval to market access for gene therapy products (GTPs): An integrative review in the US, EU5, Japan and China

Abstract

Background

This study aimed to summarize the current practices and mechanisms of market access, pricing and reimbursements for gene therapy products (GTPs) in major jurisdictions, and to identify the key barriers and facilitators affecting the translation of GTPs from regulatory approval to market access across the countries.

Methods

An integrated scoping review was conducted to identify publicly available literature and documents on the marketing access, pricing and reimbursement of GTPs under the PRISMA-ScR guidelines. Key barriers and potential enablers were identified and thematically analyzed using the Consolidated Framework for Implementation Research (CFIR).

Results

Thirty-four studies published between 2020 and May 2025 were included in this study. A total of 21 GTPs had received market authorization from the FDA, EMA, PMDA, or NMPA, targeting four major disease areas: genetic diseases (n = 8), hematologic disorders (n = 7), cancer-related indications (n = 5), and vascular diseases (n = 1). Despite growing approvals, substantial variation exists across jurisdictions in terms of access, pricing, and reimbursement pathways. Commonly reported challenges include concerns over budget impact and affordability (n = 25), uncertainty in clinical evidence (n = 24), limited value assessment frameworks (n = 17), lack of clearly defined reimbursement pathways (n = 17), misalignment between regulatory requirements and real-world implementation capacity (n = 15), and insufficient delivery infrastructure (n = 12). To address these barriers, 15 studies proposed potential solutions involving five areas: cross-country regulatory alignment and processes streaming (n = 3), pricing and reimbursement reform including budget caps, annuity payments and patent buyouts (n = 12), enhanced evidence generation through RWE and adaptive trial designs (n = 5), institutional infrastructure and workforce capacity building (n = 4), and early multi-stakeholder engagement among regulators, HTA bodies, payers, healthcare providers, and patients to align expectations and accelerate access (n = 7).

Conclusion

By adopting the CFIR framework, this study has systematically identified the key challenges and potential solutions in translating GTPs from regulatory approval to patient access. To ensure effective access, it is essential to adopt context-adapted value assessment models, diversified payment mechanisms, and coordinated policy strategies to guide the implementation processes. Building on international experiences, advancing localized implementation strategies encompassing tailored value frameworks, innovative payment models, regional pilots and institutional readiness offer actionable pathways for developing forward-looking access and reimbursement systems for GTPs.

1. Introduction

Gene therapy products (GTPs) represent a transformative category of biomedical innovation, offering durable or potentially curative treatment by delivering nucleic acid sequences to modify or correct faulty genes [1]. Since the approval of Glybera® (alipogene tiparvovec) in Europe in 2012, the number of authorized GTPs has steadily increased worldwide, indicating their clinical values especially in monogenic rare diseases, hematologic disorders, and inherited retinal conditions [2,3]. Despite their clinical promise, the real-world translation of GTPs faces a set of unique and multifaceted challenges that distinguish them from other advanced therapies. These include the unprecedented magnitude of upfront costs, uncertainty surrounding long-term safety and efficacy due to limited evidence at launch, and the difficulty of integrating these therapies into existing reimbursement and access frameworks [4,5].

For instance, Zynteglo® (betibeglogene autotemcel), an ex vivo gene therapy for β-thalassemia granted conditional approval by the European Medicines Agency (EMA) in 2019, was subsequently withdrawn from the European Union (EU) market after pricing negotiations failed to reach an agreement with public payers [6]. Similarly, in Japan, Luxturna® (voretigene neparvovec-rzyl) was approved for inherited retinal dystrophy in 2020 but experienced nearly a one-year delay before inclusion in the National Health Insurance (NHI) reimbursement list [7]. In the United States (US), patient uptake of approved GTPs remains limited by fragmented insurance coverage, the absence of coordinated payment models, and insufficient long-term real-world evidence [8].

Meanwhile, China has sought to accelerate innovation through policy-driven pathways [9]. As of 2023, it held the world's second-largest clinical pipeline of GTPs [10], and by June 2025, the National Medical Products Administration (NMPA) had approved three GTPs, including the first adeno-associated virus (AAV)-based therapy for hemophilia B in April 2025 [11]. However, none of these therapies have yet been included in China's national reimbursement drug list (NRDL), reflecting persistent challenges on affordability and access.

To address these barriers, several policy innovations have emerged across jurisdictions. The EU has promoted harmonization of clinical and health technology assessment (HTA) for advanced therapy medicinal products (ATMPs) [12], while Japan has introduced outcome-based cost-effectiveness evaluations and premium pricing schemes to balance value recognition and sustainability [13]. In the U.S., the Centers for Medicare & Medicaid Services (CMS) has launched the Cell and Gene Therapy Access Model to pilot novel risk-sharing arrangements [14]. Such initiatives highlight a growing international commitment to developing more integrated and evidence-based frameworks for equitable access to transformative therapies.

However, translating these policy innovations into consistent and effective practice remains challenging, as implementation varies widely in scope, pace and institutional alignment across jurisdictions. Existing studies have often analyzed these national approaches as standalone components, focusing on specific aspects such as regulatory standards, pricing strategies or evidentiary requirements, rather than exploring how these mechanisms interact to shape patient access [7,8,15,16].

Against this context, the objectives of this study were to: (1) summarize the current mechanisms governing market access, pricing and reimbursement (P&R) of GTPs in major jurisdictions including the U.S., the EU5, Japan, and China; and (2) identify the key barriers and potential facilitators influencing their translation from authorization to patient access. Acknowledging that national regulatory agencies (NRAs) differ in how they define and categorize GTPs [[17], [18], [19], [20]], this study primarily focused on both in vivo and ex vivo gene therapies, excluding chimeric antigen receptor T-cell (CAR-T) therapies due to their distinct clinical and regulatory characteristics [[17], [18], [19]]. The findings of this study are expected to provide a comprehensive overview of how diverse policy architectures can either enable or constrain the adoption of GTPs within sustainable healthcare systems.

2. Methods

This was an integrative scoping review conducted in compliance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis extension for Scoping Reviews (PRISMA-ScR) checklist [20] guided by the Consolidated Framework for Implementation Research (CFIR) within the discipline of implementation science [21].

2.1. Adoption of the conceptual framework

The theories, methods and frameworks of implementation science have been widely used in the investigation of effective adoption and integration of evidence-based practices, interventions, and policies in real-world settings, bridging the gaps between theory and practice [22,23]. Prior studies in the field of healthcare and public health have shown that acceptability, feasibility, and economic viability are core determinants of whether innovative practices are successfully implemented [22,23]. Although the CFIR was originally developed to examine the implementation of interventions primarily within organizational and clinical settings, it has increasingly been applied to system- and policy-level implementation questions, including the identification of determinants shaping policy implementation processes [21,24]. These factors also profoundly impact the collaborative and decision-making processes of multiple stakeholders, including regulatory authorities, healthcare providers, manufacturers, and payers [25].

In this context, the CFIR offers a structured conceptual model that supports both theoretical development and practical explanation of what works, in which contexts, and why [23]. Through its five domains (Intervention Characteristics, Outer Setting, Inner Setting, Implementation process and Characteristics of Individuals), CFIR offers a systematic lens through which policy environments and organizational capacities can be understood as shaping decision-making and implementation dynamics. By emphasizing stakeholder engagement, both internal and external contextual influences, and process-oriented and intervention components, CFIR serves as an analytical tool in identifying the critical factors, challenges and potential enablers that affect the implementation of GTP-related market access, pricing and reimbursement mechanisms.

2.2. Data retrieval and collection

The data retrieval and collection were completed in July 1, 2025 to search the information published in English and Chinese on the marketing access, pricing and reimbursement of GTPs in the United States, EU5 countries (France, Germany, Italy, Spain, and the United Kingdom), Japan, and China. Four databases (PubMed, Web of science, Scopus and Science Direct) were searched for eligible literature published from January 1, 2020 to May 8, 2025. The primary search concepts included “gene therapy products”, “access” (“market access” OR “value assessment” OR “pricing” OR “reimbursement”) and “approval” (“market authorization” OR “benefit risk”). Exclusion criteria were the unavailability of full-text articles, studies based solely on preclinical or animal models, research protocols without reported outcomes, and conference abstracts. The reference lists of included studies were reviewed to identify any potentially eligible studies. The official websites of the NRAs, HTA agencies, and healthcare reimbursement bodies were also searched for related publicly available information as of July 1, 2025. The search strategies and the official websites of the regulatory bodies consulted are listed in Appendix I.

2.3. Data extraction and analysis

Data relevant to the regulatory pathways, value assessment, pricing and reimbursement mechanisms of GTPs in the selected countries were systematically extracted and organized in an Excel table. For eligible full-text articles, the following variables were extracted into another Excel table: first author, year of publication, study design, type of therapy/or indication (if available), involved countries, as well as the main challenges and potential solutions discussed. To further explore the translational implementation of GTPs, content analysis was conducted and categorized using the CFIR, covering: (1) Outer Setting (OS), (2) Inner Setting (IS), (3) Intervention Characteristics (IC), (4) Implementation Process (PR), and (5) Individuals (IN). Additionally, identified potential solutions were coded and thematically grouped under a sixth category: (6) Solutions (SoL). A public reference manager (Zotero® software) was used to remove the duplications of records. Two authors (JS and COLU) independently screened the titles, abstracts and full texts to identify the inclusion records. Any discrepancy was resolved in consultation with another author (HH).

3. Results

3.1. Study selection

The initial search identified 1197 records. After removal due to duplications (n = 365), screening by title and abstract (n = 743) and full-text eligibility assessment (n = 56), and an addition of a publication identified through reference checking, 34 full-text eligible publications were included in this scoping review [[26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [43], [44], [45], [46], [47], [48], [49], [50], [51], [52], [53], [54], [55], [56], [57], [58], [59]] (Fig. 1).

Fig. 1.

PRISMA flow-chart of study selection.

3.2. Characteristics of included articles

Of them, 23 were country or region specific (6 on the US, 8 at European-level, 9 on the EU5 countries), and 11 adopted a comparative or integrative approach (10 analyzed the systems in the EU and the US, and 1 analyzed the systems in the EU, the US, and Japan). None of the studies examined the situation in China. In combination with the information retrieved from the official websites of NRAs, HTA agencies, and reimbursement bodies in the selected countries, a structured comparison of the regulation, value assessment, pricing mechanisms, payment and reimbursement mechanisms of GTPs across the selected jurisdictions is presented in Table 1.

Table 1.

Country practices of GTPs access & reimbursement status.

	US	EU5 (UK, Germany, France, Italy, Spain)		Japan	China
I Regulation
Approval institutions	US FDA CBER	EU EMA CAT		Japan PMDA	China NMPA CDE
Special approval pathways	RMAT designation Breakthrough therapy (BTD) Accelerated approval Priority Review Fast track (FT)	Centralized procedure via EMA PRIMA scheme Conditional marketing authorization Accelerated assessment Exceptional circumstance Hospital exemption Compassionate use Named patients (doctor's declaration) [52]		SAKIGATE designation Conditional and time-limited approval Priority Review Expedited review	Breakthrough therapy (BTD) Accelerated approval Priority Review Fast track (FT)
II Value assessment
Institutions	Institute for Clinical and Economic Review (ICER), non-governmental	UK	NICE, NHS England	●C2H under NIPH ●Expert Committee on Cost-Effectiveness Evaluation at Chuikyo ●Recommendation by Chuikyo	Not yet formally established, some cities are exploring HTA adoptions
		DE	IQWiG, G-BA
		FR	HAS TC, CEPS
		IT	Italian Medicines Agency (AIFA), CTS
		ES	Agencia Española de Medicamentos y Productos Sanitarios (AEMPS)
Mechanism	No formal national HTA, but ICER performs CEAs influences payer decisions	UK	QALY-based cost-effectiveness; Single Technology Appraisal (STA) or Highly Specialized Technologies Programme (HSTP) [53]	CEA influences prices adjustment (graded H1–H5) via Chuikyo, without affecting reimbursement eligibility	Information not found
		DE	Clinical benefit focus under the AMNOG Added Therapeutic Value Rating and Most Favorable Rating [43]
		FR	Service Médical Rendu (SMR) and Amélioration du Service Médical Rendu (ASMR) ratings
		IT	Innovativeness Recognition using the GRADE methodology
		ES	VALTERMED registry operated by the health ministry
Tools	●ICER Value Framework (QALY/evLYG) ●Budget impact models	UK	Cure Proportion Modeling and Net Health Benefits [45], Scenario Analyses and Threshold Analyses [45], QALY models and Horizon Scanning [44]	●Government-issued CEA guidelines ●Formal CEA system for selected high-cost drugs (H1–H5 grading system) ●Customized pharmacoeconomic modeling required	Information not found
		DE	IQWiG templates
		FR	Real-World Studies (RWS) Cost-Effectiveness Analysis (CEA) Multi-Criteria Decision Analysis (MCDA) for orphan drugs Single Therapeutic Indicator (ITR)
		IA	AIFA registries
		ES	A web-based information system (Valtermed) [46]
Key HTA evidence	Clinical effectiveness evidence Comparative effectiveness Quality of life metrics Health outcome and Utilities Cost inputs Budget impact analysis RWE Scenario and Sensitivity analyses Perspective (Health system, societal) Evidence Rating Matrix, incremental cost-effectiveness ratios, and price benchmarks [60]	EU	Definition of Decision Problem, Comparative Treatments, Costs and Utilities, Economic evaluation data, Time horizon, Synthesis of health effects, RWE, Perspective (Health and social care)	Clinical benefits Cost-effectiveness analysis Budget impact analysis Real-world evidence International HTA reference report	Information not found
		UK	Scope, company submission, clarification questions and answers, and ERG exploratory analyses
		DE	AMNOG dossier, IQWiG assessment, and G-BA decision
		FR	Manufacturer submission, Transparency Committee evaluation based on SMR and ASMAR ratings
		IT	Manufacturer dossier, added therapeutic benefit of medicines, quality of evidence, innovativeness status [35]
		ES	Comparative clinical evaluation (focus on identifying health problems and technologies, along with assessing efficacy and safety); non-clinical evaluation (focus on efficiency and budgetary impact, e.g. cost, ethical, organizational, social, and legal aspects)
Threshold	No official national threshold, but ICER typically uses ∼$100–150k/QALY as reference [36] Results are also presented for threshold prices up to $200,000/QALY and 200,000/per evLYG [60]	UK	Standard: £20k-£30k/QALY £50,000/QALY for End-of-Life technologies £100,000/QALY to £300,000/QALY for HST	Mainly on CEA, with 3 steps ICER thresholds on 5, 7.5 and 10 million JPY per QALY Post-launch price after other recalculation would be adjusted with CEA result, impact capped in the range of −15% to +10%, Special rule: 1.5 × ICER threshold for oncology, pediatric, and designated intractable and rare disease products	Information not found
		DE	No explicit cost-effectiveness threshold is established.
		FR	No official threshold is defined. Threshold up to €50,000 per QALY are considered in practice [36]
		IT	No official threshold is defined. Thresholds around €30,000 per QALY are suggested in studies
		ES	ICER threshold of €30,000 per QALY [36] No official threshold is defined. Thresholds around €30,000 per QALY are cited in studies
Discount type	3% for costs, LYs, and QALYs	UK	3.5% per annum	2-3% discount rate as per CEA guidelines	Information not found
		DE	3% per annum
		FR	<30 years: 2.5% >30 years: starting at 2.5% and declining to as low as 1.5% 4% per annum for GTPs
		IT	3% per annum
		ES	3% per annum
Review cycle	Payer-led renegotiation possible	UK	Approximately every 3 years or when new data become available.	Category H1, H3, H4 and H5 are selected 4 times a year. H2 is selected twice a year; CEA assessment takes ∼15-18 months and price cut decision (if any) will be announced at the next time-window	Information not found
		DE	Typically, at least one year after the initial benefit assessment
		FR	Mandatory reassessment every 5 years for outpatient medicines listed on NHI formulary.
		IT	Regular updates based on new evidence [35]
		ES	Clinical evaluation: 90 days, 20 days if the EUJCA report available; for non-clinical evaluation: 90 days extendable by 30 days [61] Data analysis and re-assessment based on “when sufficient data become available” [42]
III Pricing mechanisms
Authorities	No centralized pricing authority; manufacturers set list prices freely	UK	NHS England and NICE	MHLW Chuikyo	Manufacturers
		DE	Manufacturers, and GKV-Spitzenverband
		FR	CEPS, influenced by the European Price Guarantee
		IT	Italian Medicines Agency (AIFA), Price and Reimbursement Committee (CPR)
		ES	General Directorate for Medicines of MoH (Dirección General de Cartera Básica de Servicios del Sistema Nacional de Salud y Farmacia, DGCBSF)
Mechanisms	Methods ●Market-based pricing, manufacturers set price & subject to payer negotiations Tools ●Value-Based Pricing (VBP) ●Effective Monopoly Pricing [26] ●Patent Buyout Models [26] ●Prorated Pricing [48] ●Risk-Based Pricing [44] ●Medicaid Drug Rebate Program [41] ●Volume-based contracts with multiple State Medicaid Programs [26]	UK	●Value-based pricing and commercial negotiations ●Managed access agreements and the Innovative Medicines Fund (IMF)	Methods ●Centralized national pricing adjustment ●Similar Efficacy comparison method (SECM I/II) ●Cost accounting method (Cost Plus) ●Prices reviewed by Chuikyo Tools ●CEA-based pricing adjustment (H1–H5 system) ●Pricing premiums and adjustments ●International price referencing ●Price maintenance premium (PMP) ●Market expansion repricing ●Transparency and disclosure requirements	Methods ●Volume-based procurement to balance affordability with innovation, but not available for ATMPs
		DE	●AMNOG system ●Initial Pricing Freedom allowing reimbursement and free price setting for all new treatments during the first six months [27] ●Reference Pricing: Germany is included in the reference pricing systems of other countries, influencing the pricing strategies of MAHs [27].
		FR	Performance-based contracts and European Price Guarantee [33] Confidential price discounts [42] Set Launch Price before the negotiation with the CEPS [53]
		IT	Value-based pricing (VBP) and external reference pricing (ERP) Price-volume agreements [35]
		ES	Maximum reimbursable price nationwide of the final price [53]
Negotiation mechanisms	●IRA-based negotiation by Medicare [43] ●Patent buyout may help negotiate down prices to effective monopoly prices [26]	UK	Negotiated Discounts or Managed access agreements to address uncertainty or affordability issues for cost-effective drugs [49]	●CEA-based price adjustments (H1–H5 system), H1–H2 eligible for price premium or maintenance ●Special considerations for One-time Therapies	Information not found
		DE	Discount negotiated after 1 year of marketing [53]
		FR	Negotiation with pharmaceutical companies [33,44]
		IT	Price and Reimbursement Committee (Comitato Prezzi e Rimborso, CPR) negotiates with the company the price [51]
		ES	●Negotiation between the Price Committee and MAHs [53] ●Each Region has the authority to re-negotiate the price [53]
Price premiums	Higher launch prices for innovative drug	UK	The UK does not formally offer price premiums	Additional premiums may be applied for: ●Innovation premium (70-120%) ●Usefulness premium (5-60%) ●Marketability premium (5-20%) ●Pediatric premium (5-20%) ●Sakigake premium (10-20%) ●Specific use premium (5-20%) ●Price maintenance premium (PMP) ●Early introduction (5-10%)	Information not found
		DE	For regular benefit assessment, G-BA rating of “major” or “substantial” added benefit [42] For orphan drugs, an added benefit is assumed upon European central MA if the total expenditure is less than €50 million per year [42]
		FR	HAS assigns an ASMR rating to new drugs, indicating the level of added therapeutic benefit.
		IT	Innovative medicines benefit from dedicated funds and immediate access to regional lists, and no subject to temporary price reductions by law
		ES	For orphan drugs, a reduced mandatory price reduction (4%) applies when no generic substitute exists, acknowledging their unique status.
Re-pricing systems	No formal re-pricing system. Price changes happen via rebates or renegotiated contracts.	UK	Approximately every 3 years	Regular biennial price revisions. Trigger-based repricing due to factors like market expansion, unexpected sales growth, or new clinical evidence.	Information not found
		DE	After 1 year of market entry
		FR	Every 5 years, or earlier if new evidence emerges
		IT	No fixed schedule; re-evaluations occur as needed.
		ES	No fixed schedule; re-evaluations occur when new evidence or circumstances arise.
IV Payment & Reimbursement mechanisms
P&R decision-makers	●Public: US Centers for Medicare and Medicaid Services (CMS), Medicare/Medicaid, State Medicaid Plans [41] ●Private: Commercial insurers, self-insured employers, pharmaceutical developers	UK	NHS England	Expert Committee on Cost- Effectiveness Evaluation at MHLW/Chuikyo	●Public: NHSA and regional HSAs ●Private: commercial insurers, city private health insurers, pharmaceutical developers, charity foundations
		DE	G-BA
		FR	HAS, UNCAM
		IT	AIFA Scientific Technical Committee
		ES	AEMPS
P&R approaches	Varied across payers, dependent on insurance type and contract terms.	UK	Reimbursement based on HTA (NICE), cost-effectiveness thresholds, and negotiation via VPAG	National P&R system via Chuikyo Single-payer, government-led model	GTPs are not included in the NRDL, and the MAHs have partnered with local CHI to launch a variety of payment solutions for innovative high-value drugs
		DE	Free pricing for 1 year; reimbursement follows AMNOG benefit assessment and price negotiation with GKV-SV.
		FR	P&R based on SMR/ASMR ratings; price negotiated with CEPS.
		IT	Reimbursement based on HTA, negotiation with manufacturers [35]
		ES	Reimbursement via national and regional HTA; price set by CIPM and subject to regional access decisions
P&R mechanisms	P&R Structure ●Traditional one-time upfront ●Installments ●Annuities/Performance-based Annuities [26,41] ●Milestone-based contracts [37] ●Subscription model/pricing [37,41] Outcome-/Performance-based ●Outcomes-based payment [26,60] ●Warranties [37,41] ●Performance-based annuity [41] ●Population outcomes-based agreements [37] ●Coverage with Evidence Development [37] Financial-based ●Risk pools [37] ●Reinsurance/Stop-loss [37,60] ●Subscription as risk-carve-outs [37] ●Expenditure caps [37] ●Patent buyout/capped pricing models Access facilitation ●Early access programs (e.g. Day one) [45] ●Medicaid Pilot Programs [29,37] ●Medicare Add-On Payments (e.g., NTAP) [29] ●Collaborative Fund (e.g. Curative Gene Therapy Fund) [48] ●CMS multi-state coordinated MEAs [ICER rep] ●Payer-specific MEAs [29] ●Third-party financing intermediaries	UK	●Outcome-Based Staged Payments [43] ●Cancer Drugs Fund (CDF) ●Innovative Medicines Fund (IMF) ●Managed Access Agreements (MAAs)	●CEA-based price adjustment system (H1–H5) ●Emerging MEAs under discussion	●NRDL Category C Drug List (proposed) ●City private health insurance ●Commercial health insurance ●Outcome-based insurance ●Patient assistance program or charitable assistance
		DE	●Automatic Coverage: automatic coverage of newly marketed products by statutory health insurance fund [27] ●Risk Sharing Agreements MEA and confidential pricing agreements [27,51] ●Local MEAs and P4P schemes [42] ●NUB1 payments [40] ●Installment plan with upfront and additional annual payments (e.g Zynteglo) [53]
		FR	Initial Lump Sum and Installments [33] Performance-Based Agreements [33] Risk-Sharing Agreement [51] Entirely reimbursed by the ATU system [52] Specific “extra-list” system [44]
		IT	Outcome-based MEAs, conditional reimbursements [35] Individual-based agreements: data collected through drug registries [36] P4P payment models, paid in instalments (upon result), linked to individual patient data, and applying a confidential discount [42]
		ES	Outcome-Based Staged Payments with installments tied to specific outcomes, though details are often confidential [36]
Budget impact assessment	●ICER considers BIA in its value assessment [46] ●ICER's annual budget threshold: ∼$819 million [56] ●Considered by payers	UK	£20 million per year triggers special access agreements	No explicit budget impact threshold is publicly defined. Central in Chuikyo's CEA application and price negotiation	City medical insurance fund restrictions
		DE	€250 million: If first-year sales exceed this amount, the negotiated rebate with the statutory health insurance funds (GKV) takes effect. €20 million: For orphan drugs, exceeding this annual revenue threshold necessitates a full benefit assessment under the AMNOG process.
		FR	no explicit per-drug threshold
		IT	Beyond €500 million caps require manufacturers to reimburse the excess
		ES	No fixed threshold
Other special considerations for GTPs	●State-led gene therapy pilot programs ●Multi-state CMS risk-sharing demonstration (starting 2026) [37] ●ICER's SST value assessment framework specifically aimed to consider gene and cell therapies [50]	UK	NHS collaborates with JACIE and life sciences companies to establish and accredit treatment centers for gene therapies [53]	●Special pricing and payment policies for one-shot gene therapies ●Gene therapy tied to H1–H5 system	Information not found
		DE	Adopted extra-cost coverage systems to support hospital management for administering gene therapies [53]
		FR	Adopted extra-cost coverage systems to support the hospital management [53]
		IT	ACIE accreditation for allogeneic transplant was required for hospitals administering autologous ex-vivo gene therapies [35]
		ES	Hospital exemption scheme in place (Royal Decree 477/2014) for non-routine use of ATMPs; applies to ex-vivo gene therapies under physician responsibility

The 34 included studies comprising 4 forms of articles reported qualitative findings, including the empirical studies (n = 9) [26,27,35,[40], [41], [42],47,51,53], descriptive studies (n = 15) [29,30,34,36,38,[43], [44], [45],50,[54], [55], [56],58,59], review studies (n = 5) [28,31,33,39,46], and policy statement/perspectives (n = 5) [32,37,49,52,57]. Of the 6 included studies, four specific indications were included, covering sickle cell disease (SCD) (n = 3) [26,29,48], X-linked retinitis pigmentosa (XLRP) (n = 1) [30], somatic gene editing (SGE) (n = 1) [52] and hemophilia (n = 1) [50]. During the synthesis of findings, specific challenges across the CFIR domains were further refined and categorized, as detailed in Table 2.

Table 2.

GTPs challenges and solutions using the CFIR framework.

Author(s)/Year of publication	Study design	Type of therapy, diseases	Countries involved	CFIR categories involved∗ According to the CFIR framework, the translational implementation of GTPs into market access, pricing and reimbursement was influenced by the Outer Setting (OS), Inner Setting (IS), Intervention Characteristics (IC), Process (PR), and Individuals (IN). Solutions (SoL)
Basu, 2025 [26]	Economic modeling study	GTP, SCD	USA	OS	●Budget impact: high cost of treatment, growing size of the eligible target population ●Value assessment approaches: difficulty in quantifying economic value and setting value-based prices for GTPs
				SoL	●Patent buyout may help negotiate down prices to effective monopoly prices
Cechová et al., 2025 [27]	Empirical study	ATMP, NA	EU members	OS	●Regulatory challenge: adaptation of JCRs into national HTA processes potentially delaying early market access ●P&R pathways: member status process varies ●Cross-country disparities: variations in national HTA frameworks and reimbursement pathways
				IS	●Networks and communication: limited transparency and communication between national competent authorities (NCAs)
				IC	●Clinical evidence quality: limited efficacy data and uncertainty in long-term benefits ●Cost of intervention/care: high short-terms costs
Greco et al., 2025 [28]	Review	ATMP	USA, EU	OS	●Regulatory challenge [legal and governance]: lack of a legal framework and diverse national laws ●Regulatory challenge [transparency and accounting]: lack of transparency and confidential nature of pricing and agreements; Incompatibility with international and national accounting rules ●Value assessment approaches: Uncertainty around designing agreements and linking payment to outcomes; difficulty in assessing value for money and reaching consensus on value ●Health economic evaluation: diverse evidence requirements among HTA bodies, affecting consistency in assessment and patient outcomes ●Budget impact: financial risks include actuarial uncertainty, inability to reflect market dynamics, and volatility in price adjustment and outcome-based reward ●P&R pathways: reimbursement challenges due to risk of channeling patients, asymmetric information, long time horizons, mispricing risks, payer switching, and performance-based pricing difficulties ●MEA design and execution [negotiation]: difficulty agreeing on terms, asymmetry of information, lack of trust, political pressure, and absence of a clear taxonomy ●MEA design and execution [assessment]: uncertainty around agreement design and payment linkages to outcomes
				IS	●Administrative burdens: administrative burden, high transaction costs, and mismatches with the healthcare system structure ●Organizational readiness [infrastructure]: Lack of data infrastructure limits the feasibility of outcome-based models and real-world evidence collection ●Networks and communication:
				IC	●Clinical evidence quality: Uncertainty in defining appropriate clinical outcomes, endpoints, and success metrics; heterogeneity in HTA evidence requirements ●Evidence generation [RWE]: Challenges in collecting and managing data to generate real-world evidence; issues with payer acceptance and long timelines for demonstrating outcomes.
				PR	●Assessment [prolonged assessment duration]: time required for outcome assessment ●Assessment [strategy]: Lack of systematic approaches and strategies for evaluating and managing ATMPs ●Implementation process [data collection and management]: barriers to data sharing, data availability, and data ownership concerns in MEA implementation and monitoring
				IN	●Workforce capacity: Lack of expertise, absence of monetary incentives, and additional workload related to outcome assessment within healthcare institutions
				SoL	●Evidence generation: allow early access while evidence accumulates; prolong data collection; accept RWE; optimize R&D, and inform future research; support further evidence development; maximize patient outcomes ●Economic & pricing risks: Adjust payments based on RWE; align payment with value flow; reassess cost-effectiveness; Share financial risk; enforce budget caps; ensure predictability; reward effective treatments ●Payment & access design: Recognize long-run savings despite payer fragmentation; Link payments to outcomes; incentivize cost-effective use ●Operational & admin burden: Achieve financial protection with lower admin burden ●Cross-stakeholder process: Encourage flexible MEA design; enable cross-product deals; improve negotiation adaptability
Grilley et al., 2025 [29]	Descriptive study	GTP, SCD	USA	OS	●Regulatory challenge: policies and procedures for securing approval for CGT varies ●P&R pathways: inconsistent reimbursement rates ●Ethical and equity considerations: patient's socioeconomic status
				IS	●Administrative burdens: take months to receive payment ●Organizational readiness [financial]: financial clearance policies to ensure that prior authorization and prompt payment terms
				IC	●Cost of intervention/care: high cost of treatment, high resource intensity and extended hospitalization required for treatment ●Delivery complexity: complex chain-of-custody processes and advanced storage requirements
				PR	●Payment process: multi-million dollar receivables
				IN	●Patient affordability: financial toxicity for patients, especially those covered by Medicare or Medicaid
Hitch et al., 2025 [30]	Narrative review	GTP, X-LRP	England and Wales, France	OS	●Value assessment approaches: limited inclusion of broader value attributes (e.g. Patient HRQoL; Patient length of life; Healthcare cost-offsets; Carer HRQoL; Patient productivity; Carer productivity; Disease severity; Insurance value; Scientific spillovers; Value of hope)
Qiu et al., 2024 [31]	Review	GTP	US, DE, UK, ES, Japan	OS	●Health economic evaluation: the cost-effectiveness of gene therapies is highly sensitive to the discount rate
				IC	●Clinical evidence quality: significant limitations in clinical evidence
				SoL	●Discounting: consider the impact of alternative discount rates on ICER and ensure affordability under budget constraints
Avşar et al., 2024 [32]	Qualitative Study (expert interviews, workshop)	ATMP	EU	OS	●Regulatory challenge: lack of clear regulatory frameworks for OBAs and MEAs across Europe ●Value assessment approaches: inflexible value assessment frameworks that do not accommodate the complexities of ATMPs ●Budget impact: high upfront costs strain healthcare budgets ●MEA design and execution: complexity in designing OBAs that balance the needs of payers, providers, and patients; resource-intensive nature of OBAs, requiring substantial data collection and reassessment efforts. ●P&R pathways: unclear reimbursement pathways; and lack of clear pricing negotiation mechanisms ●Ethical and equity considerations: absence of fairness mechanisms to ensure equitable access to ATMPs ●Stakeholder collaboration: poor communication between HTA organizations and payer agencies
				IS	●Organizational readiness [HTA]: limited capacity within HTA organizations to conduct complex assessments and manage OBAs
				IC	●Clinical evidence quality: uncertainty in Long-Term Outcomes and comparative effectiveness, patient-centered outcomes and QoL ●Clinical trial design: size and design of studies that generate robust evidence, lack of data and generic measures for HRQoL ●Delivery complexity: service delivery challenges
				PR	●Implementation process: implementation burden of straining HCPs associated with OBAs and data collection
				IN	●Patient acceptability: lack of Patients' engagement with data collection
				SoL	●HTA phase: use best evidence; favor simple pricing; identify uncertainties ●OBA design phase: co-design with stakeholders; reduce burden; set interim pricing ●Data collection and reassessment phases: continue data collection; reassess once evidence matures ●Future research areas: Horizon scanning; strengthen RWE; adopt living HTA models
Bartos et al., 2024 [33]	Review	ATMP	France	OS	●Value assessment approaches: lack of transparency, the heterogeneity of the criteria, and the potential impact on innovation and access to medicines. ●Budget impact: high Prices and budgetary risks ●P&R pathways: complex and time-consuming the existing P&R frameworks ●Patient access and resource availability: selective access to reduce the target population for their treatment to keep the price high
				IS	●Organizational readiness [specialized center]: lack of well-equipped laboratories, and the contribution of hospitals
				IC	●Clinical evidence quality: uncertainty about clinical evaluations in real-life conditions, and efficacy and safety of the treatment over the long term and in a large population ●Manufacturing capacity: complex or High Manufacturing Costs
				PR	●Assessment [assessment framework]: complexity of implementing PbA, complex and time-consuming and may require changes to existing regulatory frameworks
				IN	●Workforce capacity: lack of highly qualified experts
Berishvili et al., 2024 [34]	Policy perspective	ATMP, transplantation	EU	OS	●Regulatory challenge: lack of a unified approach to policymaking in Europe ●Value assessment approaches: lack of clear value assessment frameworks for ATMPs ●Budget impact: insufficient economic returns ●Health economic evaluation: economic “valley of death”, insufficient returns lead to withdrawal of otherwise effective therapies ●P&R pathways: reimbursement constraints, unclear payment pathways and reimbursement mechanisms ●Patient access and resource availability: unequal patient access and unfair competition between HE and centrally marketed medicinal products ●Cross-country disparities: inconsistent interpretation and implementation of Hospital Exemption (HE) across the EU, and variations in reimbursement systems and policies across Europe
				IS	●Administrative burdens: bureaucratic hurdles ●Organizational readiness [financial]: lack the financial capacity to support costly clinical trials in academic institutions/charities
				IC	●Manufacturing capacity: high manufacturing costs ●Cost of intervention/care: high costs of development and approval deterring treatments from reaching the market ●Delivery complexity: complex logistics involving intercontinental cell shipments and bureaucratic delays
				PR	●Assessment [prolonged assessment duration]: complex and lengthy regulatory approval process ●P&R process [negotiations]: prolonged or unsuccessful negotiations with health systems ●Patient access [delays from reimbursement to patient access]: regions variations in reimbursement policies leading to unequal patient access
				SoL	1.Streamlining Regulatory Processes 2.Increasing Funding for ATMP Research 3.Promoting Collaborations and Partnerships 4.Establishing Pre-ATMP Facilities, providing a platform for extensive testing of products for compatibility, safety, and efficacy before full-scale GMP production and for developing and validating quality control methods, particularly potency assays. 5.Establishing Centralized ATMP Facilities 6.Enhancing the Efficiency and Accessibility of the Hospital Exemption (HE) Approval Pathway 7.Optimizing ATMP Development in Europe Through Comprehensive Data Collection and Analysis ●8. Engaging With Patients and Patient Advocacy Groups
Rivetti et al., 2024 [35]	Empirical Study	ATMP	Italy	OS	●Budget impact: elevated price tags ●P&R pathways: national price negotiation for reimbursement less straightforward and often less successful
				IS	●Administrative burdens: complex administration
				IC	●Clinical evidence quality: lack of evidence of long-term curative potential and safety ●Clinical trial design: suboptimal design of pivotal trials, single-arm with low numbers of enrolled subjects and follow-up times that do not deliver long-term data on safety and efficacy ●Manufacturing capacity: autologous nature hurdles, manufacturing failure, release of out-of-specification batches for ex-vivo GTPs ●Delivery complexity: interregional variability of drug dispensation in different hospitals, transportation bottlenecks
				PR	●Assessment [prolonged assessment duration]: lengthy EMA and national P&R evaluations delay market access ●Decision-making [prolonged regulatory timeline]: total regulatory time was 3.2 years in IT from the EMA evaluation to the P&R decision in Italy ●Patient access [delays from reimbursement to patient access]: an average of 340.6 days between official reimbursement approval and first-patient treatment in Italy and varies across different regions
				IN	●Patient affordability: distant from home (time and financial burden) ●Workforce capacity: lack of highly qualified and experienced professionals able to safely administer the drug
Drummond et al., 2023 [36]	Narrative Review	CGT	USA, EU5	OS	●Value assessment approaches: HTA process variability ●Health economic evaluation: uncertainty around the economic estimates
				IC	●Clinical evidence quality: inadequate reporting of adverse consequences and risks, immaturity of evidence and extrapolation of long-term endpoints ●Clinical trial design: use of unvalidated surrogate endpoints; lack of comparative evidence or alternative therapies; use of single-arm trials; short follow-up duration in clinical trials; limited sample sizes in clinical studies
Horrow et al., 2023 [37]	Policy insight review	GTP	USA	OS	●Regulatory challenge: legal restrictions for some payers, such as state Medicaid programs, to implement multi-year installments ●Budget impact: high upfront costs for single-dose gene therapies
				IC	●Clinical evidence quality: uncertainty regarding clinical benefits and durability of gene therapies
				PR	●P&R process [administration]: administrative complexity in tracking patient outcomes and adjusting payments.
Izeta et al., 2023 [38]	Descriptive study	ATMP	EU	OS	●P&R pathways: for-profit entities that were not reimbursed in most of those countries ●Budget impact: unsustainable therapy costs for public healthcare systems after JCA ●Cross-country disparities: lack of harmonization among EU member states ●Ethical and equity considerations: ethical considerations for pricing decisions
				IC	●Clinical evidence quality: low-quality clinical evidence and an uncertain risk-benefit balance, requiring long and extensive post-marketing studies ●Manufacturing capacity: complex manufacturing procedures, with a remarkable absence of off-the-shelf products
				PR	●P&R process [negotiation]: length of reimbursement agreement negotiations can take more than 2–3 years after centralized MA
Labry-Lima et al., 2023 [39]	Review	ATMP	EU, US	OS	●Regulatory challenge [HE]: use of hospital exemption to authorize and supervise some ATMPs without European Medicines Agency centralized approval ●Value assessment approaches [HTA]: HTA criteria set by payers for pricing and reimbursement are often opaque and inconsistent ●Health economic evaluation: risk of bias arising from conflict of interest: economic models can be highly sensitive to assumptions; industry-funded studies often estimate more favorable outcomes ●Budget impact: managing uncertainty: ATMPs are often associated with high financial and clinical uncertainty ●Cross-country disparities: Generalizability issue: between-country differences in ATMP prices and reimbursement schemes
				IC	●Clinical evidence quality: lack of evidence on efficacy and comparative effectiveness (RCTs are often infeasible in indications where standard of care is ineffective) ●Evidence generation [HRQoL]: lack of robust HRQoL data and appropriate measurement tools ●Clinical trial design: Size and design of trials: small sample sizes; modeling disease progression and extrapolation often rely on short-term or surrogate outcomes
Lee et al., 2023 [40]	Comparative review	CGT	EU5	OS	●Budget impact: budget impact on patients and national insurance ●Patient access and resource availability: accessibility of a patient to treatment
				IC	●Clinical evidence quality: clinical uncertainties coming from pharmaco-characteristics of CGTs
				SoL	●Regulatory Harmonization: align on standards (GCP, GMP, assessment guidelines, RWE use). ●Joint P&R Decisions: standardize on provisional use terms, ICER thresholds, extrapolation methods, discounting, and CEA exemptions
Quinn et al., 2023 [41]	Mixed-methods study (interview & Monte Carlo simulation)	CGT	USA	OS	●Regulatory challenge: MDRP and its determination of Medicaid Best Price (MBP) rebates impact on VBPs due to the risk of setting high MBP rebates based on a single patient's poor therapeutic outcome; MBP structural disincentives, covering single-patient, small-population, 3-year horizon, first-payment, unit-price problem ●Budget impact: State Medicaid plans face budget constraints ●MEA design and execution: MEA design difficulties due to the risk of triggering high immediate rebates and the complexity of reporting mechanisms ●Ethical and equity considerations: lack of fairness mechanisms
				SoL	●Simulated recommendations: multiple best prices, national pooling, bundled sales
Rejon-Parrilla et al., 2023 [42]	Narrative review (survey-based)	ATMP	France, Germany, Italy, Spain	OS	●P&R pathways: considerable variation exists in P&R arrangements (e.g., P4P, discounts, caps); and lack of transparency and clarity in P4P schemes ●Cross-country disparities: variation in the approaches used by individual countries ●External collaboration: lack of provision for collaboration on post-launch evidence generation (PLEG)
Vokinger et al., 2023 [43]	Review	GTP	US, EU	OS	●Regulatory challenge: differences in approved indications between the FDA and EMA ●Value assessment approaches: market access and value recognition ●Health economic evaluation: high added therapeutic value ●P&R pathways: negotiation mechanisms not aligned with the high cost of GTPs ●Budget impact: upfront financial burden ●Patient access and resource availability: price and access issues
				IS	●Administrative burdens: need for repeat administrations
				IC	●Clinical evidence quality: uncertainty regarding long-term effects
Mebarki et al., 2022 [44]	Review	ATMP	EU, France	OS	●Budget impact: financial sustainability for healthcare centers and health insurance
				IC	●Clinical evidence quality: limited data on long-term efficacy and safety ●Manufacturing capacity: difficulty in standardizing manufacturing processes ●Cost of intervention/care: higher real patient hospitalization cost ●Delivery complexity: high heterogeneity of ATMPs
Sabatini et al., 2022 [45]	Narrative Review	CGT	US, EU	OS	●Regulatory challenge: legal, regulatory, and operational complexities ●Value assessment approaches: determining fair and value-based prices ●Health economic evaluation: challenges for HTA bodies and payers in evaluating cost-effectiveness ●Budget impact: long-term budget impact
				IS	●Administrative burdens: compatibility with existing systems ●Organizational readiness [specialized center]: special infrastructural and logistical considerations for biological products, including shorter shelf lives, greater temperature sensitivities, and increased complexity and cost related to purity and identity testing
				IC	●Clinical evidence quality: comparative effectiveness (benchmarking versus the price of approved drugs in the same indication); clinical data uncertainty regarding the long-term efficacy and safety; quantification of long-term benefits ●Cost of intervention/care: high upfront costs
Simoens et al., 2022 [46]	Review	ATMP	EU, US	OS	●Regulatory challenge [guidance]: need for methodological guidelines on how to address the limitations of clinical evidence ●Health economic evaluation: lack of framework adopted by payers' under-value ATMPs, e.g. value of cure and scientific spill-overs ●Budget impact: Budget impact associated with reimbursing ATMPs primarily raises the problem of needing to make budgetary adjustments and pay large sums at once, rather than affordability per se
				IC	●Clinical evidence quality: immature clinical evidence at the time of initial reimbursement decision ●Clinical trial design: study design features such as open-label, single-arm trials, small sample sizes, heterogeneous patient populations, surrogate outcomes, and limited follow-up duration
				SoL	●Economic evaluation: offset high costs with long-term savings and full value consideration ●Payment models: Choose single vs. spread payments based on disease characteristics ●OBA roadmap: develop stakeholder-driven guides for OBA design (data, outcomes, IT, etc) ●International cooperation: strengthen cross-border collaboration on HTA, pricing, and access infrastructure
Ten et al., 2022 [47]	Comparative study	ATMP	England, Netherlands USA, EU	OS	●Value assessment approaches: distribution of key HTA considerations across various bodies ●Health economic evaluation: high ICERs and uncertainties in survival extrapolation ●P&R pathways: limited application of novel payment models ●Budget impact: financial risk and budget constrain ●External engagement: communication issues between different bodies involved in reimbursement decisions
				IS	●Organizational readiness [specialized center]: only allowing administration in specialist centers
				IC	●Clinical evidence quality: lack of comparative data, long-term effectiveness and safety evidence or retreatment data: uncertainties following from clinical data (primary outcome in the cost-effectiveness analysis differs from trial, use of proxy data), assumptions (cure and survival assumptions), and methods (indirect comparison, extrapolation, insufficient robust analysis, utility measurement) ●Cost of intervention/care: high upfront costs
				IN	●Patient acceptability: patient engagement ●Workforce capacity: need for staff training to treat and handle adverse events
				SoL	●Evidence handling: use additional sensitivity analyses, justify methods, incorporate alternative data (RWE, literature, historical) ●Implementation support: develop risk mitigation plans, conduct additional trials, and provide training/materials for clinicians and patients
Tessema et al., 2022 [48]	Description study	GTP, SCD	USA	OS	●Value assessment approaches: challenges in pricing models not being scalable to common conditions such as SCD ●P&R pathways: lack of clear payment paths for high-cost gene therapies; absence of mature mechanisms for negotiating prices that consider public funding contributions and health equity ●Budget impact: high upfront costs strain budgets for Medicaid ●Patient access and resource availability: restricted access to treatments due to high cost or systemic barriers ●Ethical and equity considerations:GTPs pricing and access may exacerbate existing racial health disparities
Champion et al., 2021 [49]	Commentary	ATMP	Wales, part of UK	OS	●Regulatory challenge: narrow license indication ●Health economic evaluation: high ICERs and associated uncertainty ●Budget impact: significant budget impact ●External engagement: coordination between different bodies
				IS	●Organizational readiness [specialized center]: limited number of designated centers for ATMP delivery ●Networks and communication: service coordination
				IC	●Clinical evidence quality: lack of long-term outcome data, including HRQoL and survival; reliance on surrogate endpoints ●Clinical trial design: significant bias due to reliance on indirect comparisons using historical controls ●Manufacturing capacity: complex production of ATMPs ●Cost of intervention/care: high costs; total costs to the NHS service far exceed the drug acquisition costs ●Delivery complexity: transportation and processing across multiple countries
Garrison et al., 2021 [50]	Description study	GTP, Hemophilia	USA	OS	●Value assessment approaches: challenges in modeling the value of cost offsets due to large up-front costs and potential long-term savings, and difficulty in projecting and contractually supporting value-based pricing given uncertain long-term outcomes ●Health economic evaluation: uncertainty around the appropriate perspective of economic evaluation, especially when GTPs may impact both direct and indirect costs ●Patient access and resource availability: perspective selection
				IC	●Clinical evidence generation: immaturity of evidence and lack of a consensus definition of “cure”, particularly in hemophilia ●Clinical evidence quality: limited follow-up data for assessing long-term benefits of gene therapies, and limitations of traditional QOL measures in hemophilia ●Clinical trial design: absence of randomized controlled trials; comparative effectiveness often based on single-arm trials ●Cost of intervention/care: high cost of advanced therapies such as gene therapy products
				SoL	●Treatment effect: base durability assumptions on clinical and biological evidence; collect RWE post-approval ●Data inputs: use synthetic controls, self-controlled trial data ●QoL measurement: add disease-specific items (e.g., hemophilia) to generic QoL tools; assess CoreHem and PROs ●Cost assessment: use real-world comparator costs for offset estimation ●Payment models: explore outcome-based contracting ●Perspective: include both healthcare and societal perspectives
Gozzo et al., 2021 [51]	Comparative study	ATMP	FR, GE, IT	OS	●P&R pathways: uncertainty in pricing and reimbursement decisions ●Budget impact: concerns about the affordability of health-care systems ●Ethical and equity considerations: patient access inequalities among european countries
				IS	●Administrative burdens: ATMP management and administration requirements ●Organizational readiness [specialized center]: need for specialized centers for ATMP administration
				IC	●Clinical evidence quality: incomplete evidence to determine their value ●Clinical trial design: lack of well-designed clinical trials in terms of sample size, use of comparators, and availability of long-term data
Rigter et al., 2021 [52]	Viewpoint	Somatic gene editing (SGE)	EU	OS	●Regulatory challenge: SGE does not neatly fall into any clear category for regulation by current legislative systems; lack of transparency in hospital exemption route ●Health economic evaluation: higher than often cited thresholds for cost-effectiveness ●P&R pathways: not clearly defined at the EU level ●Budget impact: budget impact exists ●Patient access and resource availability: market exclusivity and affordability ●Ethical and equity considerations: equity and accessibility; compassionate use does not incentivize commercial development
				IS	●Administrative burdens: require adequately trained personnel, monitoring, and evaluating results according to SOPs ●Organizational readiness [specialized center]: limit the number of treatment centers to foster expertise
				IC	●Manufacturing capacity: produced under GMP using standardized protocols ●Cost of intervention/care: high development costs
				PR	●Assessment [resource burden]: lengthy and labor-intensive, impacting pricing of drugs ●Decision-making [prolonged regulatory timeline]: lengthy decision cycle
				IN	●Workforce capacity: adequately trained personnel
Ronco et al., 2021 [53]	Comparative study	ATMP	UK, GE, FR, IT, ES	OS	●Value assessment approaches: uncertainty on the risk–benefit profile of ATMPs and their sustainability over time ●P&R pathways: reimbursement status of ATMPs heterogenous ●Cross-country disparities: P&R process is different across countries, this makes the reimbursement status of ATMPs heterogenous
				SoL	●Stakeholder engagement: promote early dialogue among HTA bodies, payers, the industry, and other stakeholders ●Value assessment: emphasize long-term and societal perspectives in evaluating value and budget impact ●Payment models: adopt annuity schemes to frame expenditures as investments
Tunis et al., 2021 [54]	Retrospective study	CGT	US, EU	OS	●P&R pathways [coverage restrictions]: [US] coverage restrictions include patient subgroup restrictions (89%), site-of-care restrictions (17%), and prescriber requirements (28%). ●P&R pathways [transparency]: [US] lack transparency regarding the rationale for specific clinical coverage restrictions ●MEA design and execution: OBAs' operational burden and limited availability of meaningful outcome measures and lack of clear pathways for MEAs and risk-sharing arrangements in some regions ●Budget impact: concerns over the cumulative financial impact on healthcare budgets due to multiple GTPs and overall affordability ●Patient access and resource availability: [US] high variability in coverage restrictions among different health plans ●Cross-country disparities: P&R decisions vary significantly across countries and health plans ●External engagement: assessment procedures are often unclear and inconsistent
				IC	●Evidence generation [P&R data]: limited evidence at the time of approval creates challenges for value assessment, reimbursement, and payment models. ●Clinical evidence quality uncertainty: limited evidence and concerns over the durability of effect, lack of high-quality, long-term, real-world data on interventions, higher uncertainty in benefit-risk assessments due to indirect comparisons and historical controls ●Clinical trial design: Single-arm trials, short-term trials, surrogate endpoints ●Manufacturing capacity: complex and costly manufacturing processes ●Cost of intervention/care: high cost of therapies
				PR	●Assessment [prolonged assessment duration]: unclear and inconsistent assessment procedures
Angelis et al., 2020 [55]	Description study	CGT	USA, EU	OS	●Value assessment approaches: assessment of the cost of a disease and its financial implications through cost-of-illness studies, including direct healthcare costs, indirect productivity losses, and intangible psychosocial burdens for patients and carers ●Health economic evaluation: efficiency (in terms of costs, benefits and cost-effectiveness) and affordability (in terms of budget impact), together with relevant HTA agencies' experience ●Budget impact: budgetary considerations and value for money
				IC	●Clinical evidence quality: high uncertainty around long-term benefits; the extrapolation of clinical trial data over the long term was not supported by current evidence, as long-term treatment-effect persistence remains unknown ●Clinical trial design: small sample size in clinical trials
				SoL	●Efficiency (cost estimation): adjust comparator costs; include side effects; harmonize cost methods and data ●Efficiency (benefit estimation): use multi-horizon models, probabilistic analysis, advanced modeling, and MCDA ●Efficiency (ICER adjustment): apply unified ICER rules, re-price offsets, cap QALY at max WTP, use MCDA ●Affordability: define budget thresholds; adjust ICERs or budgets; apply MCDA for trade-offs ●Financial risk (uncertainty): use outcome-based payment models (e.g., performance-based agreements) ●Financial risk (high budget impact): implement installment plans, credit/loan schemes, and payer reinsurance
Coyle et al., 2020 [56]	Description study	CGT	USA, EU	OS	●Value assessment approaches: value determination ●Budget impact: long-term social care costs, as well as financial effects for immediate family members ●P&R pathways: mechanisms to address affordability and sustainability, ●Ethical and equity considerations: public health trade-offs
				IC	●Clinical evidence quality: uncertainty about clinical effectiveness; need for surrogate endpoints in C&G therapies ●Clinical trial design: absence of randomized controlled trials (RCTs) for decision-making ●Manufacturing capacity: Bioproduction of live products ●Delivery complexity: transport and logistical procedures
				SoL	●Trial design: promote adaptive designs, propensity scoring, early HTA dialogue, and protocol transparency ●Value framework: include broader elements (severity, hope, spillover, insurance value, etc.) ●Decision criteria: apply QALY weightings, MCDA, and sliding-scale cost-effectiveness thresholds ●Pricing: use ICER, QALY-based caps, and re-pricing of cost-offsets ●Discounting: ensure transparency in discount rates; conduct sensitivity analyses
Gonçalves, 2020 [57]	Editorial	ATMP	EU5	OS	●Value assessment approaches: integration of ethics in HTA to improve accountability and decision-making; traditional value assessment frameworks may not adequately capture the long-term benefits of ATMPs ●P&R pathways: fragmentation and variation in pricing and reimbursement frameworks ●Budget impact: BIA fails to capture savings in the social care budget (e.g., rehabilitation or long-term care); time horizons are too short (typically 1–2 years) ●Ethical and equity considerations: ethical issues include gene therapy, gene editing, and patient data sharing
				IS	●Administrative burdens: significant clinical and administrative burden
				IC	●Clinical evidence quality: lack of long-term data at launch ●Clinical trial design: inadequate timeframe of clinical trials ●Manufacturing capacity: high manufacturing costs ●Delivery complexity: complex interventional procedures for administration
				PR	●Market access [time burden]: time-consuming HTA and market access strategy ●P&R process [negotiations]: challenges in negotiating acceptable prices
				IN	●Payer attitudes: payers may be reluctant to support the high costs of ATMPs
Goula et al., 2020 [58]	Description analysis	ATMP	EU	OS	●Regulatory challenge: specific regulatory and pharmacovigilance demands; Bio-vigilance system and quality standards
				IS	●Organizational readiness [facility/equipment]: need for equipment, know-how and appropriate facilities to support ATMP delivery
				IC	●Manufacturing capacity: complex manufacturing and challenges in compliance with GMP standards ●Cost of intervention/care: high up-front cost associated with ATMP development and delivery ●Delivery complexity: highly specific storage requirements including short shelf life
				IN	●HCP attitudes: uncertainties discourage physicians from recommending ATMPs; patient administration and follow-up burdens the treating physic ●Workforce capacity: limited ability to select experienced staff at both clinical and institutional levels due to limited use of these products
				SoL	●Biovigilance System: develop as a learning organization with ongoing staff training, interdisciplinary communication, and a culture of quality and safety
Salvatore, 2020 [59]	Description analysis	ATMP	EU	OS	●Regulatory challenge: length and complexity of the regulatory procedures ●Budget impact: high range costs of reimbursement for national health systems ●Patient access and resource availability: unavailability of the product to a wider category of patients who could benefit ●Cross-country disparities: restriction of use within one Member State limits cross-border patient access ●External engagement: lack of sufficient funding to support and compensate R&D activity
				IS	●Organizational readiness: For small and medium enterprises, lack of regulatory expertise to navigate MA procedures
				IC	●Clinical evidence quality: unavailability of enough evidence of comparable clinical effectiveness; unavailability of clinical trial data under hospital exemption to demonstrate benefit-risk ●Clinical trial design: complexity of clinical trials, including difficulties identifying relevant animal models and designing studies for small populations ●Manufacturing capacity: lack of standardization in manufacturing procedures ●Cost of intervention/care: high treatment costs ●Delivery complexity: challenges in supply chain management
				IN	●Workforce capacity: pressure on Qualified Persons (QPs) ●Developers' perspective: ATMP researchers and developers are confronted with additional hurdles
				SoL	●Multiple-stakeholder collaboration: strengthen cooperation among regulators, industry, academia, and research institutions ●SME/Academic support: establish EMA service hub for guidance and training for SMEs and spin-offs ●Early R&D advice and transparency: enable parallel EMA-HTA advice for SMEs and academia to engage early with investors, and promote early sharing of data and development plans for ATMPs ●Regulatory clarity: apply stricter interpretation of hospital exemption clauses

3.3. Overview of approved GTPs and reimbursement status across jurisdictions

As of May 2025, a total of 21 GTPs targeting four major disease areas (genetic diseases (n = 8), hematologic disorders (n = 7), cancer-related conditions (n = 5), and vascular diseases (n = 1)) had been granted marketing authorization by the FDA, EMA, PMDA or NMPA (Fig. 2). Further information about the regulatory designations and reimbursement details are provided in Appendix II. In the EU, a total of 13 GTPs were approved, with 1 product expired in 2017, 1 product withdrawn in 2022, and 9 GTPs received varying degrees of reimbursement in EU5. In the US, 14 GTPs have been approved, with 1 withdrawn in 2024 and the remaining 13 reimbursed by private payers (including 3 being part of the CMS CGT access pilot program that has been temporarily paused). In Japan, 5 products have received reimbursement from the NHI. In China, no GTPs have yet achieved reimbursement status.

Fig. 2.

Approved GTPs' marketing and P&R status in the selected countries.

3.4. GTPs pricing, payment and reimbursement pathways in key markets

3.4.1. The US

In the US, GTPs are regulated by the Center for Biologics Evaluation and Research (CBER) under the FDA which offers expedited approval pathways to facilitate faster approval. However, unlike many jurisdictions, the US lacks a national HTA body. Instead, clinical and economic evaluation is largely market-driven and conducted by academic institutions or independent third-party organizations such as the Institute for Clinical and Economic Review (ICER) [14,36]. While the U.S. employs a free pricing system, manufacturers often engage in payer-specific negotiations with commercial insurers, Medicare, Medicaid, and hospital systems [26,41,60].

The US is actively exploring innovative payment models such as: (1) fair pricing strategies (e.g. discounts, ethical considerations, shared-savings models), (2) budget impact mitigation (e.g. stop-loss insurance, reinsurance, subscription models, federal carve-out benefits), and (3) clinical uncertainty management (e.g. performance-based rebates and staged payments, warranties) [41]. Nevertheless, the New Technology Add-On Payment (NTAP) mechanism under Medicare offered limited financial support leaving hospitals bearing substantial costs and imposing a major barrier to GTP accessibility [29].

3.4.2. EU5 countries

3.4.2.1. European Union

In the EU, all GTPs are subject to centralized marketing authorization by the EMA. Pricing and reimbursement decisions are made at the national level, relying on HTA frameworks that incorporate cost-effectiveness analysis, budget impact modeling, and international reference pricing. To promote cross-country HTA coordination, the European Network for Health Technology Assessment (EUnetHTA) was established in 2006, along with the EUnetHTA Core Model supervised under the EU HTA Regulation in 2021 [40]. In 2025, the Joint Clinical Assessments (JCA) mechanism, coordinated by EU-level HTA bodies, was implemented under the EU Regulation 2021/2282 to streamline clinical value evaluations while reducing duplication at the national level [27].

3.4.2.2. United Kingdom

In the UK, GTPs require approval from the Medicines and Healthcare Products Regulatory Agency (MHRA), followed by HTA by the National Institute for Health and Care Excellence (NICE) [38,52]. NICE primarily assesses reimbursement eligibility based on the incremental cost-effectiveness ratios (ICERs). For rare diseases, NICE employs a specialized Highly Specialized Technologies (HST) pathway, which allows for a higher willingness-to-pay threshold (up to £300,000/QALY) [53].

Once positively recommended by NICE, therapies are eligible for inclusion in the National Health Service (NHS) funding, typically with negotiated commercial discounts or outcome-based payment models to mitigate financial risk. For therapies with limited clinical evidence but urgent clinical need, NICE may grant conditional coverage through mechanisms such as the Cancer Drugs Fund (CDF) or Managed Access Agreements (MAAs) [36], which enable early access while collecting real-world evidence (RWE) to inform future reappraisal.

3.4.2.3. Germany

In Germany, GTPs with EMA authorization or national approval enter the market through the AMNOG (Arzneimittelmarkt-Neuordnungsgesetz) process [43]. Manufacturers are entitled to free-pricing during the first six months of GTP market entry. Concurrently, the Federal Joint Committee (G-BA) determines the level of additional benefit (major, considerable, minor), based on the results of HTA performed by the Institute for Quality and Efficiency in Health Care (IQWiG) or the G-BA itself. In case of orphan drug or significant added benefit, the manufacturer may negotiate a premium price with the National Association of Statutory Health Insurance Funds (GKV-Spitzenverband) [27].

For products with lower benefit ratings, pricing is typically benchmarked against the annual treatment costs of comparators. If price negotiations fail within six months, an arbitration board will determine the reimbursed price to be applied from the seventh month after launch [27,53]. Outcome-based reimbursement mechanisms are also implemented so that payers may request partial refunds or waive remaining payments should predefined clinical outcomes not be met. Post-marketing surveillance through national patient registries is also in place to assess real-world effectiveness.

3.4.2.4. France

In France, after EMA authorization, to inform the reimbursement decision and the negotiated price, GTPs undergo evaluation by the Haute Autorité de Santé (HAS) through two core processes: (1) Service Médical Rendu (SMR), which determines reimbursement eligibility based on contribution to public health, and (2) Amélioration du Service Médical Rendu (ASMR), which assesses added clinical benefits compared to existing treatments on a scale from I (major improvement) to V (no improvement) [33,42,53].

Before formal MA is granted, products may be made available through the Autorisation Temporaire d’Utilization (ATU) program [52]. During the ATU period, manufacturers may freely set prices within predefined caps, and are required to collect RWE to support HTA assessments. Following MA, pricing is set by the Economic Committee for Health Products (CEPS) based on ASMR grades and other conditional reimbursement agreements (e.g. rebates or paybacks).

3.4.2.5. Italy

In Italy, GTPs approved by EMA undergo HTA procedures coordinated by the Italian Medicines Agency (AIFA) [35]. The Technical Scientific Committee (CTS) is responsible for evaluating clinical benefit and indications, while the Pricing and Reimbursement Committee (CPR) conducts price negotiations and budget assessments. GTPs may be categorized under Class A (fully reimbursed) or Class H (hospital-only use), determining the scope of national coverage [35,36]. Centralized pricing negotiations with a focus on clinical effectiveness, budget impact, and target population size are applied.

For ultra-expensive rare disease therapies, AIFA adopts payment-by-results (PbR) mechanisms and installment-based payment models to ensure fiscal sustainability [42]. All reimbursed therapies are registered in the national patient database to enable longitudinal outcome tracking for real-time budget oversight and post-market price adjustments. If expected outcomes are not achieved, partial refunds or waived future payments are applicable through risk-sharing agreements.

3.4.2.6. Spain

In Spain, EMA-approved GTPs are subject to the national P&R review by the Interministerial Committee on Pricing of Medicines (CIPM), with final reimbursement decisions implemented at the regional level. Historically, the Therapeutic Positioning Report (IPT) served as the primary HTA output, which reportedly lacked transparency, governance and methodological best practices [61]. In 2024, the Ministry of Health issued a draft royal decree regulating the evaluation of HTA and published a new strategy for the medicine pricing and reimbursement system [61,62].

Despite ongoing structural improvements, the influence of economic criteria (e.g. the social value and the impact on health-related quality of life) remains [36,53]. While CIPM establishs maximum allowable prices, individual hospitals are permitted to negotiate bespoke financial agreements with manufacturers or establish tailored formularies. Performance-based reimbursement models (e.g. paybacks or outcome-based non-payment) are in place [36]. The Valtermed system was launched to monitor clinical outcomes and inform payment performance. Real-world evidence is also used to inform reimbursement schemes [42].

3.4.3. Japan

In Japan, GTPs classified as regenerative medical products can be approved through accelerated pathways (e.g. Sakigake designation) under the Pharmaceuticals and Medical Devices (PMD) Act. After approval, P&R decisions are determined by the Ministry of Health, Labour and Welfare (MHLW) and the Central Social Insurance Medical Council (Chuikyo) through a government-led process. The Drug Pricing Organization (DPO) calculates the price based on a combination of cost-based methods (cost calculation formula) and comparative methods (Type I/II cost-effectiveness-based external reference pricing) [63].

Since 2022, Japan has introduced systems such as the Sakigake Add-on and Special Usage Premiums to encourage therapies with high innovation, pediatric indications, rare disease targets, or breakthrough clinical efficacy [63]. In 2024, Chuikyo implemented comprehensive Drug Pricing Reform to promote the early launch of innovative drugs, adjust the prices of certain imported drugs, simplify the Price Maintenance Premium (PMP) and revise eligibility criteria for existing premium schemes [64].

The reimbursement process includes two rounds of pricing negotiations. In the first round, the Economic Division of the MHLW's Health Policy Bureau proposes a preliminary price based on internal expert evaluations. In the second round, the DPO determined the final price based on the cost and comparison principle for inclusion in the NHI price list. Japan also implements a dynamic pricing system which adjusts prices regularly based on market surveys and enlist new drugs in the NHI reimbursement list up to four times each year [65].

3.4.4. China

In China, GTPs are classified as a subclass of ATMPs according to guidelines issued in June 2025 and are regulated by the Center for Drug Evaluation (CDE) under the National Medical Products Administration (NMPA), which provides accelerated pathways such as breakthrough therapy designation, conditional approval, and priority review to facilitate the development and approval of GTPs [66]. Although China has not yet established a unified HTA agency, HTA has played an important role in the adjustment of the National Reimbursement Drug List (NRDL), led by the National Healthcare Security Administration (NHSA), which is jointly responsible for pricing and reimbursement with regional healthcare security administrations (HSAs).

As of 2025, GTPs have not yet been included in the NRDL. However, referring to the experience of high-cost therapies such as CAR-T, marketing authorization holders have improved accessibility through city-level private insurance, commercial health insurance, efficacy insurance contracts and patient assistance programs [67]. On July 1, 2025, the NHSA and National Health Commission released the “Measures to Support the High-Quality Development of Innovative Drugs”, introducing a Commercial Insurance Drug List. Targeting high-cost therapies like GTPs, the policy promotes flexible pricing, broader institutional use, commercial payer engagement, and R&D support via national insurance data to improve access and market entry [68].

3.5. Challenges in translating GTPs from regulatory approval to market access

Major categories of challenges affecting the translation of GTPs from regulatory approval to market access included: budget impact and affordability concerns (n = 25) [26,28,[32], [33], [34], [35],[37], [38], [39], [40], [41],[43], [44], [45], [46], [47], [48], [49],51,52,[54], [55], [56], [57],59], uncertainty of clinical evidence quality (n = 24) [27,28,[31], [32], [33],[35], [36], [37], [38], [39], [40],[43], [44], [45], [46], [47],[49], [50], [51],[54], [55], [56], [57],59], lack of value assessment approaches (n = 17) [26,28,30,[32], [33], [34],36,39,43,45,47,48,50,53,[55], [56], [57]], unclear P&R pathways (n = 17) [[27], [28], [29],[32], [33], [34], [35],38,42,43,47,48,[51], [52], [53], [54],57], misalignment between regulatory requirements and real-world practice needs (n = 15) [[27], [28], [29],32,34,37,39,41,43,45,46,49,52,58,59], and insufficient organizational readiness within healthcare systems (n = 12) [28,29,[32], [33], [34],45,47,49,51,52,58,59]. Specific challenges are mapped with the CFIR domain as depicted in Table 3.

Table 3.

Challenges in translating GTPs from regulatory approval to market access.

Domains	Challenges identified	USA (n = 6)	EU5 (n = 17)	Mixed (n = 11)	Total (n = 34)
Outer Setting	Regulatory challenge	3	7	5	15
	Value assessment approaches	3	6	8	17
	Health economic evaluation	1	3	10	14
	P&R pathways	2	11	4	17
	Budget impact and affordability	4	12	9	25
	Managed entry agreements	1	1	2	4
	Cross-country disparities	0	6	2	8
	Stakeholder collaboration/engagement	0	4	2	6
	Ethical and equity considerations	3	5	1	9
	Patient access and resource availability	2	5	2	9
Inner Setting	Administrative burdens	1	5	3	9
	Organizational readiness	1	8	3	12
	Networks and communication	0	2	1	3
Intervention	Clinical evidence quality	2	11	11	24
	Clinical trial design	1	6	6	13
	Manufacturing capacity	0	10	2	12
	Cost of intervention/care	2	7	3	12
	Delivery complexity	1	8	1	10
	Evidence generation and collection	1	0	3	4
Process	Assessment process	0	4	2	6
	Market access pathway	0	1	0	1
	P&R process	2	3	0	5
	Decision-making timeline	0	2	0	2
	Patient accesses	0	2	0	2
	Implementation process	0	1	1	2
Individuals	HCP attitudes	0	1	0	1
	Payer attitudes	0	1	0	1
	Patient acceptability	0	1	1	2
	Patient affordability	1	1	0	2
	Workforce capacity	0	5	2	7
	Developers' attitudes	0	1	0	1

3.5.1. Outer setting

Challenges arising from outer settings primarily reflected jurisdictional policy heterogeneity and systemic constraints. Budget impact and affordability driven by high upfront costs, and the financial risk from short-term budget impact analysis were mostly discussed. Divergent regulatory pathways and policies such as inconsistent application of hospital exemption provisions and delayed translation of JCA into national-level decisions also impeded early market access [[27], [28], [29],32,34,37,39,41,43,45,46,49,52,58,59]. Inconsistencies in the negotiation of payment mechanisms (e.g. performance-based agreements) in the pricing and reimbursement pathways were fragmented, non-transparent, time-consuming and highly complicated [27,[32], [33], [34], [35],38,42,43,47,52,53,57]. As exemplified in the US, restrictive payer coverage policies, non-transparent clinical eligibility criteria, and the absence of mature mechanisms for price negotiations negatively impacted on health equity [28,29,48,54].

The inability to capture long-term clinical benefits, therapeutic value, and broader societal impacts of GTPs (e.g. reduced caregiver burden, productivity gains, and scientific spillovers) were frequently discussed [26,32,43,50,53,[55], [56], [57]]. Value-based pricing (VBP) mechanisms were complicated by clinical uncertainty, limited data, and the heterogeneity of different payers [28,39,45,50,57]. A standardized and transparent approaches towards health economic evaluations was lacking [28,31,34,36,39,43,[45], [46], [47],49,50,52,55,56].

HTA was further complicated by divergent economic evidence requirements, reliance on modeling assumptions, and a lack of long-term efficacy data [33,34,36,39,47]. Ethical and equity-related issues (n = 9) [29,32,38,41,48,51,52,56,57], inequalities in patient accessibility due to resource availability and insurance schemes (n = 9) [33,34,40,43,48,50,52,54,59], insufficient stakeholder coordination (n = 6) [32,42,47,49,54,59] and suboptimal implementation of the managed entry agreements (MEAs) (n = 4) were also identified as recurrent challenges [28,32,41,54].

3.5.2. Inner setting

There were 3 primary challenges in the inner settings. Firstly, organizational readiness referred to the lack of appropriate infrastructure, management capabilities, technical resources, institutional support required to meet the storage, handling, and patient follow-up requirements of GTPs constraining geographical access for patients [28,29,[32], [33], [34],45,47,49,51,52,58,59]. Secondly, the administrative burdens included complex and repetitive authorization processes, bureaucratic hurdles, misalignment with existing healthcare system structures, and the pressure on healthcare providers and administrative staff imposed by the rigorous standard operating procedures (SOPs) [28,29,34,35,43,45,51,52,57]. Thirdly, weak inter-organizational communication and coordination between NRAs and healthcare institutions were highlighted, hindering effective implementation and management of GTP-related processes [27,28,49].

3.5.3. Intervention characteristics

Intervention challenges primarily focused on the immaturity and limited quality of clinical evidence at the time of regulatory approval or initial reimbursement decisions. The lack of long-term data on safety, efficacy, durable clinical benefits, relevant endpoints, and health-related quality of life (HRQoL) [27,31,32,[35], [36], [37],39,43,44,47,[49], [50], [51],55,57], together with the absence of comparative effectiveness studies due to the lack of a standard-of-care control arm [28,33,38,39,[45], [46], [47],[54], [55], [56],59], further contributed to uncertainties in clinical value.

Inadequate reporting of potential risks and adverse consequences warranted extensive and prolonged post-marketing studies [36,38]. Limitations of clinical trial design were mainly due to open-label, single-arm designs with small sample sizes, short follow-up durations, and unvalidated or surrogate endpoints [32,35,36,39,46,[49], [50], [51],[54], [55], [56], [57],59]. Data collection and evidence generation is further complicated by a lack of consensus on core definitions for key outcomes [28,39,50,54].

Manufacturing-related challenges included high production costs, the absence of off-the-shelf products, and technically demanding manufacturing processes necessitating compliance with strict standard operating procedures (SOPs) or Good Manufacturing Practice (GMP) standards [[33], [34], [35],38,44,49,52,54,[56], [57], [58], [59]]. Logistic and service delivery complexities referred to transportation and bureaucratic delays, strict and product-specific storage requirements, interregional inconsistencies in drug dispensing practices, and logistical bottlenecks in delivery infrastructure [29,32,34,35,44,49,[56], [57], [58], [59]]. High development and treatment costs were also considered as major deterrent [27,29,34,44,45,47,49,50,52,54,58,59].

3.5.4. Process challenges

Process-related challenges primarily concerned the inefficiency and complexity of assessment, implementation, and reimbursement processes. During assessment processes, prolonged evaluation timelines [28,34,35,54], a lack of systematic approaches for evaluating GTPs [28,33], labor-intensive procedures [52], and time-consuming HTAs [57] collectively contributed to delays in market access. The P&R processes were challenged by lengthy or unsuccessful negotiations with health systems, discrepancies in aligning acceptable pricing and high account receivables, and the complexity in tracking patient outcomes for performance-based payment adjustments [34,37,38,57]. For example, the total regulatory time from EMA evaluation to the final P&R decision in Italy was 3.2 years, with an additional average of 340.6 days between official reimbursement approval and the first patient treatment [35]. Concerns about data collection infrastructure, data availability, and data ownership issues as implementation barriers had also been discussed [28,32].

3.5.5. Individuals

At individual-level, challenges arose particularly about workforce capacity (e.g. adequately trained HCPs to administer, monitor, and manage ATMPs) [28,33,35,47,52,58,59]. Some HCPs were either skeptical about long-term outcomes or bothered by the administrative burdens associated with prolonged patient monitoring [58]. From the patient perspective, high out-of-pocket expenses [32,35], treatment acceptability [32,47], uncertainty surrounding long-term benefits, and burdens associated with participation in data collection or long-term follow-up might discourage patients’ willingness to initiate or maintain treatment. Payers could also be doubtful about high upfront costs associated with ATMPs [57,59], while developers faced regulatory and institutional complexities that undermined their motivation and engagement [59].

3.6. Potential solutions

Potential solutions can be categorized into the following five key areas. Firstly, harmonization of standards across jurisdictions, including Good Clinical Practice (GCP), GMP, and RWE frameworks had been called for [40], and streamlining regulatory processes by having clearer guidance and stricter interpretation of HE provisions to reduce prolonged evaluation periods were recommended [34,59]. Secondly, optimization of pricing and reimbursement strategies (e.g. patent buyouts, budget caps, dynamic HTA models, RWE-based adaptive payment schemes, flexible MEA design, and stakeholder-led roadmaps for OBAs to manage financial risk [32,46]) were repeatedly explored [26,28,31,32,34,40,41,46,50,53,55,56]. Standardization across ICERs thresholds, discounting methods, and provisional use terms [31,40,56], and collective procurement approaches (e.g. multiple best prices, national pooling, bundled sales) [41] were recommended. Thirdly, the quality and applicability of clinical and economic data should be improved with strengthening RWE collection [28,32,47,50] and adaptive and innovative trial designs (including the use of synthetic controls and broader endpoints such as disease-specific quality of life (QoL), patient-reported outcomes (PROs) and societal values) [50,56].

Fourthly, institutional infrastructure investment and workforce capacity building with risk mitigation plans and training programs for both clinicians and patients could benefit organizational readiness [34,47,58,59]. Pre-ATMP centralized facilities were instrumental to conducting early compatibility testing, validating potency assays, and ensuring manufacturing readiness prior to full-scale GMP production [34]. Responsive biovigilance systems, interdisciplinary collaboration, and ongoing pharmacovigilance training should be adopted for continuous quality improvement [58]. Early multi-stakeholder engagement to enable early parallel scientific advice from regulatory and HTA bodies (e.g. support hubs for SMEs and academic developers) and structured dialogue among HTA agencies, payers, industry, clinicians, and patient advocacy groups were also important [28,34,46,50,53,56,59].

4. Discussion

This review provides a comprehensive summary of the market access, pricing and reimbursement mechanisms of GTPs in the US, EU5 countries, Japan and China. Under the guidance of the CFIR, key challenges and potential solutions in facilitating the transition from regulatory approval to patient access were identified. A conceptual framework to help stakeholders navigate the current implementation landscape of access, pricing, and reimbursement strategies of GTPs was developed (Fig. 3).

Fig. 3.

Implementation framework and elements of advancing access, pricing and reimbursement of GTPs.

4.1. Integration framework of bridging approvals and sustainable access

Striking a balance between accelerated regulatory approval and delayed reimbursement remains a common systemic challenge for all NRAs considering a significant institutional path dependence in the payment pathways. In the US, a multi-payer system dominated by commercial insurance offers flexibility to quickly respond to corporate pricing through innovative contracts [29,48]. Yet, the absence of centralized negotiation and redistribution mechanisms often leads to disparities in coverage criteria, access equity and consistency [29,41,48].

In contrast, EU5 countries rely primarily on publicly funded systems that, while more centralized and capable of available price negotiation, are constrained by fixed budgets and complex processes [27,34,38,42,53,59]. These systems often face difficulties in managing the short-term financial impact of high-cost GTPs, prompting the introduction of supplemental mechanisms such as special access funds (e.g., the UK's CDF) or performance-based contracts [36]. Japan's nationally administered universal coverage system tends to limit flexibility for novel payment arrangements [69]. In China, a dedicated value assessment and reimbursement framework for ATMPs is still lacking. Current NRDL negotiations emphasize price compression and short-term budget control, and a need for hybridized or pilot payment models to improve access to high-cost, innovative therapies is prominent [70].

How to comprehensively capture the multidimensional value of GTPs from the perspectives of patients, healthcare systems, and broader society while appropriately managing inherent evaluation uncertainties remains a challeng. Conventional HTA methodologies often undervalue the long-term societal benefits associated with successful gene therapy, such as improvements in patient quality of life, restored productivity among caregivers, and reductions in future healthcare resource utilization. For instance, in its assessment of HEMGENIX® (etranacogene dezaparvovec-drlb), ICER incorporated the productivity loss of both patients and caregivers as part of its cost-effectiveness evaluation [71]. Despite estimating only modest incremental health benefits over prophylactic Factor IX therapy, HEMGENIX® still received a B+ rating, reflecting its broader economic and social impact [71]. While GTPs may catalyze broader biomedical innovation and societal benefits, these spillover effects are seldom reflected in current HTA frameworks.

GTPs are primarily developed for rare genetic disorders, where small patient populations and ethical concerns make it difficult to conduct conventional randomized controlled trials. Consequently, pivotal evidence is often derived from single-arm designs, surrogate endpoints, and limited follow-up, leaving substantial uncertainty regarding long-term effectiveness, durability, and safety. This uncertainty is central to HTA appraisal and directly informs payer decision-making, often prompting conservative modeling assumptions (e.g., alternative durability scenarios, sensitivity analyses around extrapolation and discounting) and the adoption of risk-management mechanisms such as restricted coverage, conditional reimbursement, coverage with evidence development, and outcomes-based agreements.

Methodological and governance responses to such uncertainty increasingly emphasize multi-stakeholder engagement and the use of diverse evidence sources [72]. Recognizing these limitations, ICER's “Value Assessment Methods for High-Impact Single or Short-Term Therapies” emphasizes the importance of multi-stakeholder engagement in collecting diverse data sources and leveraging multidisciplinary collaboration for holistic evaluation [73]. Enhancing patient involvement, particularly through the integration of patient preference studies and patient-reported outcomes (PROs), has also been identified as a key strategy. For example, during the appraisal of Luxturna®, NICE extensively engaged patient advocacy groups, clinical experts, and other stakeholders [74]. This input supported the Evidence Review Group's selection of baseline comparators and endorsed the sponsor's assumptions regarding treatment durability and potential cost offsets from avoiding long-term supportive care. The appraisal committee also considered two discounting scenarios to reflect this uncertainty. In 2022, the China's NMPA issued the “Technical Guideline for Clinical Research and Development of Drugs for Rare Diseases”, which allows that single-arm studies using historical controls when robust natural history data are available, and recommends tailoring clinical endpoints based on existing treatment data [75]. When patient numbers are extremely limited and variability in disease progression or physiological status is high, adaptive designs and advanced statistical methods that maximize the utility of limited data should be encouraged.

Importantly, post-launch evidence evolution means that “approval-to-access” is not necessarily a one-directional trajectory. When post-marketing studies fail to confirm anticipated benefit, market access decisions may be revisited through price renegotiation, delisting, or non-renewal of conditional coverage, and in some cases products may be discontinued or withdrawn. For instance, Collategene (beperminogene perplasmid) in Japan was discontinued in 2024 after post-marketing evaluation failed to establish sufficient clinical efficacy and its conditional/time-limited status was not converted to full approval [76]. This experience underscores the role of reassessment mechanisms in governing access to GTPs under uncertainty. From a conceptual perspective, it also illustrates how the proposed integration framework can generate actionable insights even when the clinical value of a technology is subsequently questioned. Specifically, uncertainty in clinical validity and durability can be operationalized within the intervention characteristics domain, while the policy instruments that govern conditional approval or coverage, post-marketing evidence generation, and reassessment triggers can be mapped to the outer setting and implementation process domains. In this way, the framework accommodates both sustained access pathways and “reversal” scenarios in which initial access decisions are later modified as new evidence emerges.

Disparities in accessibility across regions, as well as limited availability of these products within healthcare institutions remain common. While the R&D and regulation of ATMPs are increasingly benefiting from international convergence, such as the EU's JCA mechanism and multilateral regulatory collaborations like Project Orbis, HTA and reimbursement status remain highly localized and fragmented, influencing the equitable global patient access. The absence of unified or mutually recognized HTA frameworks has significantly increased the data submission and negotiation burden on MAHs, and contributed to duplicative assessment efforts. For example, Zynteglo® (betibeglogene autotemcel), approved conditionally by the EMA in 2019 for transfusion-dependent β-thalassemia, failed to secure reimbursement agreements in both Germany and France and was eventually withdrawn from the European market. To collectively enhance global access to GTPs and optimize resource allocation across health systems, innovations such as shared RWE data platforms, collaborative value assessments, and joint reimbursement negotiations are needed [34,40,46].

Patient access to GTPs also critically depends on the high requirements of manufacturing and delivery infrastructures, including GMP-compliant processing, cold chain logistics, individualized preparation protocols, and seamless integration with clinical administration. However, the current global distribution of manufacturing and delivery capabilities is uneven [77,78]. Accredited manufacturing centers or qualified treatment sites are generally in short supply [43,45,47,49]. Particularly in low- and middle-resource settings, inadequate infrastructure, insufficiently trained clinical personnel, and weak quality assurance systems further exacerbate geographic inequities. GTPs treatment centers should comply with stringent accreditation criteria set by national authorities, often implemented through international certification procedures such as the JACIE (Joint Accreditation Committee ISCT-Europe and EBMT) to ensure the safety, consistency, and quality of clinical delivery for GTPs [53].

4.2. Policy implications for emerging markets

By drawing on international experiences in advancing value assessment, payment mechanism, regional pilot programs, and institutional readiness, emerging markets have the potential to develop a more forward-looking access and reimbursement framework to address the core questions of “who pays” and “how to pay”.

4.2.1. Establishing a localized, value-based assessment framework

Building on international models, developing a multi-dimensional HTA pathway dedicated for GTPs that integrates RWD/RWE and broader societal value is the utmost important. Life-cycle cost-effectiveness models that incorporate long-term impacts on patients’ quality of life, caregiver burden, labor productivity, health equity, and multi-period risk-adjusted approaches, should be introduced to inform evidence-based pricing and reimbursement negotiations, and broader payer decision-making under the NRDL framework.

4.2.2. Developing diversified and risk-sharing payment mechanisms

Adaptive payment models incorporating commercial insurance and charitable foundations to support a multi-payer system contribute to shared financial responsibility and alleviate the budgetary strain on the public system. This should be coupled with innovative and flexible payment pathways such as performance-based payment agreements, installment-based payment schemes, capped total payments, and dynamic price adjustments based on real-world outcomes.

4.2.3. Advancing regional pilots for regulatory and payment coordination

Regional pilot programs can help catalyze broader national reforms in access, pricing, and cross-border collaboration, contributing to the development of a national access and payment framework for GTPs. Under national policy guidance, local governments may be able to leverage the regulatory flexibility of free trade zones and designated demonstration areas to explore early access schemes and innovative pricing mechanisms, while also enabling strategic platforms for RWE generation and performance-based payment evaluation to support more evidence-informed decision-making in national reimbursement negotiations. For instance, the rare disease drug pilot zone in the Tianzhu Free Trade Zone and the Hainan's Boao Lecheng International Medical Tourism Pilot Zone in China were set to become frontiers for regulatory and payment innovations for novel therapies [79,80].

4.2.4. Strengthening institutional preparedness and delivery capacity

Ensuring institutional readiness for GTP implementation requires a systematic approach targeting key components such as on-site manufacturing capabilities, quality control systems, and intra-hospital organizational infrastructure and workforce readiness. Healthcare institutions should adopt internationally recognized standards, such as the JACIE accreditation framework, to establish multidisciplinary teams and implement closed-loop management processes that cover patient selection, treatment delivery, and post-treatment monitoring [81]. Building a standardized pathway from product receipt to clinical delivery will be critical in enabling the scalable deployment and international integration of innovative gene therapies.

5. Strengths and limitations

One of the strengths of this review is its structured analysis of GTPs’ market access, pricing, and reimbursement across major jurisdictions, guided by the implementation science framework to facilitate a more standardized and implementation-oriented evidence base. Additionally, by capturing both international policy practices and system-level barriers, the findings could be used to guide context-sensitive strategy design and stakeholder dialogue to promote sustainable and equitable access to GTPs. There are still some limitations in our review. One of the limitations was publication bias, as the availability of national-level data is often constrained by the evolving nature of policies and ongoing regional pilot programs possibly resulting in time lags or information gaps. Not using the names of specific GTPs in the search may have limited the retrieval of product-specific evidence or grey literature, particularly related to individual therapies. Secondly, while the use of the CFIR enabled a structured qualitative mapping of barriers and enablers, it was not originally designed as a macro-level policy analysis framework and may not fully capture political and agenda-setting dimensions of policy processes that are emphasized in approaches such as the Health Policy Triangle. Future research may therefore consider integrating CFIR with complementary policy frameworks to better examine the dynamics of policy formulation and stakeholder power relations underlying market access decisions. In addition, this review did not involve quantitative comparisons of HTA outcomes or pricing decisions across jurisdictions or individual products. Future research may incorporate product-level data to enable more robust cross-jurisdictional comparisons, including comparative effectiveness and cost-effectiveness analyses. Finally, this study primarily focused on the experiences of the United States, EU5 countries, Japan, and China. The exclusion of other regulatory and reimbursement practices may limit the generalizability of the findings and future studies should consider expanding the study targets.

6. Conclusion

There is an urgent need for context-adapted value assessment models, diversified payment schemes, and coordinated policy strategies to improve access to GTPs. Advancing localized implementation strategies encompassing tailored value frameworks, innovative payment models, regional pilots and institutional readiness offer actionable pathways for developing forward-looking access and reimbursement systems for GTPs.

Consent to participate

Not applicable.

Ethics approval

Not applicable.

Consent for publication

Not applicable.

Author contributions

JS and COLU planned and designed the study. JS, COLU, HH were responsible for data management and analysis. JS and COLU drafted the manuscript. COLU and HH critically reviewed and revised the manuscript. All authors read and approved the final manuscript.

Funding

This work was supported by a grant from University of Macau ( MYRG-GRG2024-00147-ICMS-UMDF, MYRG-CRG2024-00024-ICMS-IAS), State Key Laboratory of Mechanism and Quality of Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, and Centre for Pharmaceutical Regulatory Sciences, University of Macau.

Declaration of competing interest

The authors declare that they have no competing interests.

Appendix.

Appendix I. Data retrieval strategy to conduct the scoping review

Source	Research equations
Search strategy: A AND (B OR C)
Databases	Search concepts A (GTPs)	Search concepts B (Access)	Search concepts C (Approval)
PubMed	●Biological Therapy[Mesh] ●Regenerative Medicine[Mesh] ●Advanced therapy medicinal product∗ ●Receptors, Antigen, T-Cell[Mesh] ●Cell engineering[Mesh]	Market access ●Market access ●Market entry ●Patient access ●Managed entry agreement Value assessment ●Technology Assessment, Biomedical[Mesh] ●Costs and Cost Analysis[Mesh] ●Economics[Mesh] ●Economic evaluation Payment & Reimbursement ●Pricing ●Price∗ ●Payer ●Reimbursement ●Performance based ●Financial based ●Performance-based ●Financial-based	Market authorization ●Drug Approval[Mesh] ●Market authorization ●Market authorization Benefit risk ●Risk Assessment[Mesh]
Web of science	●TI=(cell and gene therap∗) ●TI=(gene-based therap∗) ●TI=(cell-based therap∗) ●TI=(stem cell therap∗) ●TI=(tissue-based therap∗) ●TI=(tissue engineering) ●TI=(tissue therap∗) ●TI=(gene therap∗) ●TI=(genetic therap∗) ●TI=(cellular therap∗) ●TI=(cell therap∗) ●TI=(biological therap∗) ●TI=(advanced therapy medicinal product∗) ●TI=(advanced therap∗) ●TI=(regenerative medicine∗) ●TI=(regenerative therap∗) ●TI=(ATMP∗) ●TI=(CAR T)	Market access ●TI=(market access) ●TI=(market entry) ●TI=(patient access) ●TI=(managed entry agreement) Value assessment ●TI=(health technology assessment∗) ●TI=(economic evaluation) ●TI=(cost∗) ●TI=(cost-effective∗) ●TI=(cost effective∗) ●TI=(cost-benefit) ●TI=(cost benefit) ●TI=(cost-utility) ●TI=(cost utility) ●TI=(cost-utilities) ●TI=(cost utilities) ●TI=(cost-analysis) ●TI=(cost analyses) Payment & Reimbursement ●TI=(pricing) ●TI=(price∗) ●TI=(payer) ●TI=(reimbursement) ●TI=(performance-based) ●TI=(performance based) ●TI=(financial-based) ●TI=(financial based)	Market authorization ●TI=(market authorization) ●TI=(market authorization) ●TI=(regulatory approval) ●TI=(regulatory evaluation) ●TI=(drug approval) Benefit risk ●TI=(benefit-risk assessment∗) ●TI=(benefit risk assessment∗)
Scopus	●TI=(cell therap∗) ●TI=(cellular therap∗) ●TI=(genetic therap∗) ●TI=(gene therap∗) ●TI(tissue therap∗) ●TI=(cell and gene therap∗) ●TI=(genetic engineering) ●TI=(cell-based therap∗) ●TI=(gene-based therap∗) ●TI=(tissue-based therap∗) ●TI=(advanced therapy medicinal product∗) ●TI=(advanced therap∗) ●TI=(regenerative medicine∗) ●TI=(regenerative therap∗) ●TI=(ATMP∗) ●TI=(CAR T)	Market access ●TI=(market access) ●TI=(market entry) ●TI=(patient access) ●TI=(managed entry agreement) Value assessment ●TI=(health technology assessment∗) ●TI=(economic evaluation) ●TI=(cost∗) Payment & Reimbursement ●TI=(pricing) ●TI=(pric∗) ●TI=(payer) ●TI=(reimbursement) ●TI=(performance based) ●TI=(financial based)	Market authorization ●TI=(approval∗) ●TI=(regulatory evaluation) ●TI=(market authorization) ●TI=(market authorization) Benefit risk ●TI=(benefit risk assessment∗)
ScienceDirect	●cell therapy [title] ●gene therapy [title] ●tissue therapy [title] ●regenerative therapy [title]	●market access [title] ●cost [title] ●price[title]	●approval [title] ●assessment [title]
Search in the official government and professional organization websites
Websites	United States ●United Food and Drug Administration (FDA), https://www.fda.gov/ ●Centers for Medicare & Medicaid Services (CMS), https://www.cms.gov/ ●Institute for Clinical and Economic Review (ICER), https://icer.org/
	European Union ●European Medicines Agency (EMA) in the European Union, https://www.ema.europa.eu/en
	United Kingdom ●Medicines and Healthcare products Regulatory Agency (MHRA), https://www.gov.uk/government/organisations/medicines-and-healthcare-products-regulatory-agency ●National Institute for Health and Care Excellence (NICE), https://www.nice.org.uk/ ●NHS England, Market Access & Reimbursement, https://www.england.nhs.uk/commissioning/
	Germany ●Federal Institute for Drugs and Medical Devices (BfArM),https://www.bfarm.de/ ●Institute for Quality and Efficiency in Health Care (IQWiG), https://www.iqwig.de/ ●G-BA (Federal Joint Committee), https://www.g-ba.de/
	France ●French National Agency for Medicines and Health Products Safety (ANSM), https://www.ansm.sante.fr/ ●Haute Autorité de Santé (HAS), https://www.has-sante.fr/ ●L'Assurance Maladie (National Health Insurance), https://www.ameli.fr/
	Italy ●Italian Medicines Agency (AIFA), https://www.aifa.gov.it/ ●Italian National Health Service (Servizio Sanitario Nazionale - SSN), https://www.salute.gov.it/
	Spain ●Spanish Agency of Medicines and Medical Devices (AEMPS), https://www.aemps.gob.es/ ●Ministry of Health – Reimbursement Information, https://www.sanidad.gob.es/
	Japan ●Pharmaceuticals and Medical Devices Agency (PMDA), http://www.pmda.go.jp/ ●Ministry of Health, Labour and Welfare (MHLW), https://www.mhlw.go.jp/
	China ●National Medical Products Administration (NMPA), https://www.nmpa.gov.cn/ ●National Healthcare Security Administration (NHSA), https://www.nhsa.gov.cn/ ●Center for Drug Evaluation (CDE), https://www.cde.org.cn/
	Other sources if available

Abbreviation: Title (TI).

Appendix II: The access and reimbursement status of the approved GTPs in the US, EU5, Japan and China

GTP brand name	Target indication	MoA	Regulatory approval status (time, pathway)				Access and reimbursement status
			EMA	FDA	PMDA	NMPA	EU5	USA	Japan	China
Genetic Diseases
Elevidys	DMD	AAV-based		Jun 2023, Accelerated approval	May 2025, SAKIGAKE Designation Conditional and time-limited approval			Private reimbursed; CMS CGT access pilot paused
Glybera	LPLD	AAV-based	Oct 2012, MA Oct 2017, expired				HTA in DE/FR, but not reimbursed
Libmeldy/Lenmeldy	MLD	Lentiviral-based	Dec 2020, ATMP and orphan drug	Mar 2024, BLA approval			Fully reimbursed in UK/DE/IT/ES FR in evaluation	Private reimbursed
Luxturna	Retinal dystrophy	AAV2-based	Nov 2018, ATMP and orphan drug	Dec 2017, Orphan drug, Priority review, and Breakthrough therapy	Jun 2023, Orphan Regenerative Medical Product Designation		Fully reimbursed in UK/DE/FR/ES,Restricted label in IT	Private reimbursed	Reimbursed
Strimvelis	ADA-SCID	γ-Retroviral-based	May 2016, ATMP
Upstaza/Kebilidi	AADC Deficiency	AAV2-based	Jul 2022, ATMP under additional monitoring and Orphan designation, Exceptional circumstances	Nov 2024, Accelerated approval, Orphan drug, Rare disease priority review			Fully reimbursed in UK/DE/FR/IT ES not reimbursed	Private insurer pending review
Vyjuvek	RDEB	HSV-based	Apr 2025, ATMP under additional monitoring and Orphan designation, PRIMA	May 2023, Orphan Drug, Fast Track, RMAT, and Priority Review designations
Zolgensma	SMA	AAV9-based	May 2020, ATMP under additional monitoring, Orphan designation, Conditional approval, PRIMA	May 2019, Breakthrough therapy, Accelerated approval, Fast Track, Priority Review designations	Mar 2020, Priority review (Orphan) SAKIGAKE		Fully reimbursed in DE, FR in EAP phase Restricted label in UK/IT/ES	Private reimbursed	Reimbursed with HTA assessment
Hematologic Disorders
BBM-H90/信玖凝	Hemophilia B	rAAV-based				Apr 2025, Priority Review
Casgevy	TDT/SCD	CRISPR/Cas9 Gene-Edited	Feb 2024, ATMP under additional monitoring, Orphan designation, Conditional approval, PRIMA	Dec 2023, Orphan Drug, Fast Track, RMAT, and Priority Review designations			NHS temp funding DE/FR in eval	Private reimbursed; CMS CGT access pilot paused
Durveqtix/Beqvez	Hemophilia B	AAV5-based	Jul 2024, ATMP under additional monitoring, Conditional approval, PRIMA	Apr 2024, BLA approval			Pending P&R decision	Withdrawal from market
Hemgenix	Hemophilia B	AAV5-based	Feb 2023, ATMP under additional monitoring, Orphan designation, Conditional approval, PRIMA	Nov 2022, Breakthrough therapy, Accelerated approval, Priority Review designations			NHS temp funding DE/FR low rating	Private reimbursed
Lyfgenia	SCD	Lentiviral-based		Dec 2023, Orphan Drug, Fast Track, RMAT, and Priority Review designations				Private reimbursed; CMS CGT access pilot paused
Roctavian	Hemophilia A	AAV5-based	Aug 2022, ATMP under additional monitoring, Orphan designation, Conditional approval, PRIMA	Jun 2023, Breakthrough therapy			Fully reimbursed in DE/IT; UK/FR/ES in evaluation	Private reimbursed with clinical criteria restriction
Zynteglo	TDT	Lentiviral-based	May 2019, ATMP with accelerated assessment, conditional approval, PRIME Mar 2022, withdrawed	Aug 2022, Breakthrough therapy, Orphan Drug, Fast Track, Priority Review, Accelerated approval			Withdrawal from market	Limited reimbursement
Vascular Diseases
Collategene	CLI	Plasmid DNA with HGF			2019 Conditional and time-limited approval				NHI Reimbursed
Cancer-related
Adstiladrin	BCG-unresponsive, NMIBC	Non-replicating adenovirus vector-based		Dec 2022, Breakthrough therapy, Fast Track, Priority Review				Private reimbursed
Delytact	Malignant Glioma	HSV-1-based oncolytic virus			2021 Priority review (Orphan) SAKIGATE Conditional and time-limited approval				NHI Reimbursed
Gendicine/今又生	HNSCC	Adenovirus-p53				2003, MA
Imlygic	Melanoma	HSV-1-based oncolytic virus	Dec 2015, ATMP approval	Oct 2015, Fast Track, Priority Review			Fully reimbursed in DE	Private reimbursed
Oncorine/安科瑞	Multiple solid tumors	Adenovirus E1B-deleted adenovirus				2005, MA

Appendix n. Supplementary data

The following are the Supplementary data to this article.

Data availability

Publicly available datasets were analyzed in this study.