The complex price setting and reimbursement of non-industrial advanced therapy medicinal products.

Introduction

Advanced Therapy Medicinal Products (ATMPs) are “medicines for human use that are based on genes, tissues or cells” [ 1 ]. They are, in most cases, indicated to treat rare diseases or patients with unmet medical needs, administered in a single shot, and intended to offer long term benefits to patients. The combination of these features (small patient populations, single administration and long-term benefits), associated with the often-immature evidence supporting their pricing and reimbursement (P&R) submissions, pose important challenges for payers having to make difficult resource allocation decisions [ 2 ]. ATMPs are made up of live tissue or cells and therefore they are characterized by specific manufacturing and quality control requirements and product delivery solutions [ 3 ]. Industrial ATMPs are developed by commercial entities. Before they can be commercialized they must obtain a marketing authorization, which in the European Union (EU) is granted by the European Medicine Agency (EMA), and their price and coverage are negotiated by each Member State [ 4 ]. However, academia dominates early-stage development of ATMPs [ 5 ], and about 25% of currently approved industrial ATMPs originate from research performed in specialized academic facilities [ 6 ]. Furthermore, the hospital exemption (HE) created a regulatory environment where clinical academic groups with public support or the support of non-for-profit funds are covering the entire development process through to becoming license holders [ 7 ]; these are non-industrial or academic ATMPs.

The HE regulates access to non-industrial or academic ATMPs under defined conditions. Their development and manufacture is at small scale, not for commercial purposes and at a national level only [ 8 ]. The HE clause changed the European ATMP regulation EC1394/2007 to Directive 2001/83/EC, to allow manufacturing of ATMPs outside the standard centralized marketing authorization, under the following conditions: “ ATMP is prepared on a non-routine basis according to specific quality standards , and used within the same Member State in a hospital under the exclusive professional responsibility of a medical practitioner , in order to comply with an individual medical prescription for a custom-made product for an individual patient ” and “ Manufacturing of these products shall be authorized by the competent authority of the Member State. Member States shall ensure that national traceability and pharmacovigilance requirements as well as the specific quality standards at Community level in respect of advanced therapy medicinal products for which authorization is required pursuant to Regulation” [ 9 ]. There are many different interpretations of the ATMP Regulation EC1394/2007 across Member States, which results in differences in how it is implemented in national legislations, in aspects such as the level of clarity, level of R&D activities of ATMPs carried out by national academic and commercial organizations, transparency level, among others [ 7 , 10 ].

In 2022, the EMA launched a pilot to provide enhanced support to academic and non-profit developers of ATMPs that respond to unmet medical needs [ 11 ]. In response to their potential to offer innovative solutions to unmet needs, but also of the particular needs for enhanced support of academic and non-profit developers, the pilot (1) supports applicants in meeting regulatory standards in terms of quality, safety and efficacy, and (2) focusses on identifying and addressing possible enhancements to existing regulatory instruments and support available to applicants. The pilot will also help applicants with the planning and submission of marketing authorization requests if required [ 12 , 13 ].

The reimbursement landscape for ATMPs under the HE is also heterogeneous across Member States [ 7 , 14 ]. In Spain, the prices of non-industrial ATMPs are set based on the standardized form specifically developed for this purpose [ 15 ]. In some countries in the EU, funding for HE products is structured through Diagnosis Related Groups (DRGs) [ 16 ], and in others reimbursement rates are negotiated or determined by health insurers [ 17 ]. It is worth mentioning that a recent study on the HE identifies the Spanish guideline as an example of good practice by “providing a cost template for clear and transparent price calculations” [ 14 ]. However, the guideline has not been analyzed before in peer reviewed literature, nor has it been compared to alternative approaches applied in other countries [ 18 ]. Additionally, information on the perceptions of players involved in the setting of prices of non-industrial therapies about the completeness of this document is lacking. Therefore, the primary objective of this paper is to describe the landscape around the P&R of ATMPs that are developed by academic developers in Spain by analysing the Spanish costing guideline (i.e. its origins, the cost elements to be included and the costing methodology to be followed to estimate the cost of each element included). The secondary objective is to describe the P&R landscape for ATMPs developed under HE by academic and non-profit developers in Europe.

Methodology

To date, to our knowledge, none of the ATMPs that were included in the EMA pilot to support academic and non-profit developers of ATMPs have yet completed the process that leads to obtaining a central European marketing authorization. Hence, to our knowledge, no industrial ATMPs with an academic sponsor without an industrial partner has negotiated prices outside of the contained local environment the HE regulates. Nevertheless, we have identified two examples of academic ATMPs having obtained a price in the member State where they were approved under the HE [ 19 ]. Given that, in nature, our research, mostly prospective and exploratory, adopted a mixed-method approach, combining information gathering through a literature review and website search without a formal systematic search, and stakeholder involvement through online interviews and email follow-ups. The literature review was mainly based on snowballing approach [ 20 ]. We also did a targeted review of selected literature based on our knowledge of the field and targeted ad-hoc searches of relevant sources to inform this work, including peer-reviewed literature and grey literature (including reports and articles by specialist or mainstream news-outlets). This search was conducted in PubMed, Google Scholar, EMA and the Spanish Agency for Medicines and Health Products (AEMPS) websites using terms including “hospital exemption”, “advanced therapy medicinal products”, “pricing and reimbursement”, “pricing”. Due to the very limited literature found specifically addressing pricing and reimbursement of advanced therapies under the HE, we completed the review with interviews and email enquiries with experts on the topic. We performed this as follows. ZS developed semi-structured questionnaire based on the gaps identified in the literature reviewed. The questionnaire (see Supplementary Material) served as the basis for the interviews conducted online and for email enquiries to complement findings from the literature. We contacted different stakeholders from a range of disciplines and backgrounds, including experts with management, industry, and policy-making backgrounds with expertise on the topic from five European countries (Italy, Norway, Poland, Spain and the Netherlands). Experts from Spain were contacted to provide their insights on the Spanish costing template, those from the Netherlands and Norway were contacted because through our research we identified that these countries were developing academic CAR-T therapies [ 21 , 22 ] (one of which has a public list price in Spain). Experts from Italy were contacted because an Italian ATMP is part of the EMA pilot program for academic and not-for-profit developers [ 12 ] and those from Poland were contacted to understand how the margin in their cost-plus pricing system is calculated. Online interviews were prepared and held mainly by ZS and JCRP, while JE provided support and senior oversight to this line of research in the project. All information regarding type of stakeholder, their expertise and route for engagement are summarized in Table 1 . In total, we performed three online interviews, received one semi-structured questionnaire and received four answers by email. Five interviewees were contacted more than once (in one case because we did not receive any answer even the interviewee agreed to participate and in four cases because of some additional questions). The manuscript was revised by three interviewees.

We used the information gathered through the literature, interviews, semi-structured questionnaire and email contact to identify potential areas for further development in the approaches to reimbursing non-industrial ATMPs identified.

Results

The Results section is organized as follows. First, we focus on describing the P&R landscape of non-industrial ATMPs in Spain, the origins of the Spanish costing guideline to inform pricing of HE-ATMPs, the costing elements included in and briefly describe cost-plus approach the guideline is based on. Second, we provide a summary of P&R mechanisms applied across a sample of European Union (EU)Member States.

Pricing & reimbursement of non-industrial ATMPs in Spain

The standardized form for calculating the price of non-industrially manufactured ATMPs was approved by the Interterritorial Council of the Spanish National Health System on October 14, 2019 [ 15 ], and one of the interviewees explained that it is an adaptation of the form developed by the Advanced Therapies Unit of the Madrid Regional Health Department. Although the form was applied for the first time in pricing of the cell therapy (i.e., NC1), many of its concepts also apply to gene therapy and tissue-based therapies (which, in essence, are similar to gene therapies). Before the standardized form was approved, there was no formally established and published mechanism for determining how to set the price of a publicly produced medicinal product. However, in the Region of Madrid, several hospitals had non-industrial ATMPs under development (e.g., Hospital La Paz was developing a CAR-T therapy, and Hospital Puerta de Hierro in Majadahonda was developing the NC1 cell therapy [ 23 ], which at the time was the most advanced). This interviewee continued to explain that to develop the form, the entire process of evidence collection and manufacturing was reviewed—from patient selection (i.e., type of patients, sample collection, estimated hospital stay, etc.), to drug manufacturing (i.e., the processing of the raw material, cryopreservation, final product quality controls, batch release, etc.), costs of the production unit itself (i.e., costs of maintaining the rooms where the process takes place), and additional costs due to production failures (i.e., how treatment failures were estimated based on previous clinical trials), among others. To complete price applications, once the form is completed, price requests must be accompanied by a value dossier. This dossier describes and justifies, on the one hand, all cost elements captured in the standardised form and, on the other, the monetary value assigned to each cost component is indicated but not justified (for example, why production failures are estimated at 10% and not 30%, why the hourly rate of each technician is valued at a certain amount, which products are accounted for to fulfil appropriate quality controls to justify a specific cost for that step, etc.). The information in the dossier is confidential, and its length and the justifications in it are as comprehensive as required by the Ministry of Health. Additionally, the dossier must incorporate the evidence used to demonstrate to the regulator that the preclinical and clinical data are of sufficient quality to assess a positive benefit/risk balance, supporting a positive decision to allow the use of the ATMP under the HE [ 24 ]. Currently, there are five non-industrial ATMPs approved under the HE in Spain [ 25 ], of which four are reimbursed and two have an established price that was determined using the Standardized form. The developer of CEMTROCELL is a private company; therefore the therapy is paid out-of-pocket [ 26 ]. The public list prices of ARI-0002 h and the artificial human skin have not been negotiated yet (Table 2 ).

The Spanish pricing guideline for non-industrial ATMPs includes direct manufacturing costs. Table 3 shows the main cost components included in the guideline. The full guideline translated into English can be found in Supplementary Material.

Once the total costs of developing the therapy have been calculated (sum of items 1–9 in Table 1 ), the next step is to estimate the number of patients over whom these costs will be spread. In the case of NC1, AEMPS together with the hospital (i.e., the owner of the therapy) established the maximum number of patients to be treated during the first two years. This number was used to estimate the cost of production unit and ultimately the price of the therapy.

Several interviewees agreed that the costing guideline does not include the costs of clinical trials, because that money has been granted by the public sector for research and, therefore, cannot be charged to the final product. “On one hand, even if the product had not been released in the end, the money would have been spent anyway and, therefore, cannot be allocated to the final product. On the other hand, it cannot be allocated to the final product because it would have to be divided among the number of vials to be sold, and that is something unknown”. However, another interviewee argued that “the reward for successful development makes sense where there is an economic incentive in developing the therapy. In a public context this would not normally apply regardless of the patient population to be treated”. In one of the interviews, an inconsistency was identified between the costs the interviewee reported as absent in the guideline and the costs that are actually included in it. One of the interviewees reported the transport of intermediate costs (i.e., starting material, e.g., patient’s lymphocyte T when the aphaeresis is carried out at the patient’s home institution) as absent. According to this interviewee, “excluding transportation costs might be an issue, since in that case, the ‘hospital exemption holder’ needs to bill the transport separately. This may lead to certain difficulties, as the centres purchasing the final product might be surprised to see transport costs billed separately, given that when they buy the commercial product, transport is included. Therefore, it is important that the costing guideline includes not only production costs, but also the logistics costs associated with product delivery”. However, the guideline does include the transport of both the intermediate and the final product (see Sect. 2.6 of Supplementary Material). Furthermore, the guideline also does not include long-term follow-up costs (i.e., pharmacovigilance).

The final section of the guideline includes an incentive for future research. The incentive is progressive by tiers, following this scheme: tier 1, up to €20,000, receives a 5% incentive; tier 2, from €20,001 to €30,000, receives a 3% incentive; tier 3, from €30,001 to €40,000, receives a 2% incentive; and tier 4, above €40,000, receives a 1% incentive [ 15 ]. In other words, if the total sum of all costs on the sheet is €47,700, a progressive incentive of €1,576.97 is applied, and the proposed price would be €49,276.97 (Table 4 ).

One of the interviewees claims that the research incentive was capped at a maximum of 5% for two main reasons: (1) there were concerns that a higher incentive would substantially increase the price of NC1; and (2) because the therapy was developed largely within the public sector, most of the associated development costs had already been covered with public funds. The same interviewee continues explaining that over time, as the issue has been examined in greater depth, it has become clear that the development of NC1 also involved private contributions (from foundations, individuals, associations, etc.). Therefore, to ensure that future projects initiated in the public sector can continue to advance—without depending on external entities whose support may not be sustained over time—it would be necessary to increase that percentage.

Pricing & reimbursement of non-industrial ATMPs within a sample of European countries.

We analysed P&R landscape of non-industrial ATMPs in 19 EU Member States. HE-ATMPs are reimbursed by the National Health Service (NHS) in 10 countries (Austria, Denmark, Estonia, Finland, Germany, Ireland, Portugal, Spain, Sweden and the Netherlands). In Denmark and Sweden, the reimbursement is applied at regional level. In Germany, the “NUB Reimbursement Pathway” for funding allows hospitals to apply for the temporary reimbursement of “new and innovative diagnostic and treatment methods” that have not yet been assigned a German DRG code, provided an EMA marketing authorization application has been submitted [ 37 ]. Therefore, although NUB funding is not specific to either ATMPs or HE products, but it may provide a potential avenue for financing HE-ATMPs (it allows for limited time case-by-case charge), as it did for an autologous chondrocyte implantation (ACI) therapy. This funding is not guaranteed; it must be negotiated and renewed annually by hospitals. Additionally, the application process is highly complex. Treatments that receive a positive assessment through the NUB process may be incorporated into the German DRG system, and then be formally reimbursed with an established DRG code with a fixed rate per case [ 7 , 16 ]. It is worth noting that Germany is an outlier in the European HE landscape, with small biotech dominating rather than clinical academic groups as it is the case in the rest of Member States, and with a vast majority of HE products in Germany being tissue-engineered products, as opposed to the diverse mix of cell-, gene- and tissue-based ATMPs that are manufactured under HE in other Member States [ 7 ]. One of the interviewees explained that the Spanish market operates differently due to the lack of venture capital wealth. Pursuing this further, this interviewee described the Spanish case as an exception, as both public funding and venture capital investors are scarce. Projects are typically not investment-grade due to limited technology transfer, and a relatively small venture capital community. Nevertheless, the interviewee continued to clarify that projects that meet higher standards can still secure seed investment. In Portugal and the Netherlands, the national reimbursement of HE-ATMPs is possible, but uncommon [ 26 ]. One of the interviewees affirms that, in the Netherlands, no specific ATMP-costing/pricing policy is available. “HE-ATMPs do not have public list prices per se. They often are part of or payed for through DRGs. So knowing which DRG is used for which product gives some insight in what the price approximatley is”. Difficulties to obtain reimbursement for production costs and treatment reimbursement have been reported in The Netherlands [ 38 ]. The NHS in France is launching a national reimbursement of HE-ATMPs via annual budget al.location per patient (so called ‘forfeit’). Until the program is fully implemented, the hospitals have to cover the costs of HE products [ 26 ]. In Spain, the coverage of HE-ATMPs depends on the nature of the HE holder; the therapies are covered by the NHS if developed by public developer and paid out-of-pocket if developed by a private entity [ 26 ].

HE-ATMPs are not reimbursed in Austria, Belgium, Cyprus, Czech Republic, Italy, Lithuania, Malta, Poland and Slovenia. Out of these, Cyprus, Czech Republic and Malta have not developed any HE-ATMP so far. In Belgium, the only HE product was revoked in 2023, as a clinical trial allowing the inclusion of patients whom the HE initially was used for was initiated [ 26 ]. An interviewee claimed that in Italy, there is no formal pathway for the reimbursement of HE-ATMPs nor are there guidelines on costs that could be included in the price. Production costs are covered by the manufacturing authorisation holder (often with support of external funding) and hospitals with authorisation for use cover clinical costs. The same interviewee also stated that “Whenever a hospital asks the authorization to treat a patient under the HE, the same hospital should confirm it can cover all the related costs (or that it will get the product for free in case the owner is another entity)”.There are guidelines on how to prepare the P&R dossier that include some considerations on cost calculation, however, they are not specific for HE-ATMP [ 39 ].

Regarding costing model used for P&R decisions, the cost-based approach (i.e., no profit expected) is the most frequent among EU Member States (Denmark, Estonia, Finland, Ireland, Italy, Lithuania, Portugal and Sweden. In the Netherlands, the cost-based approach or health technology assessment is used to set the price of HE-ATMPs. In Denmark, HE pricing is also accompanied by a cost-effectiveness analysis and in Estonia, HE pricing is informed by health and budget impact in addition to cost-effectiveness analysis [ 26 ].

Poland and Spain are the only countries using cost-plus approach to inform HE pricing, i.e., it covers the manufacturing costs plus a profit margin [ 26 ]. This margin is understood as an incentive for future research and is tiered (up to 5%) in Spain [ 15 ]. One of the interviewees stated that in Poland, the margin is confidential if the HE product is developed by a private entity. We have not been able to determine what criteria are used to set the profit margin in the case of HE-ATMPs developed by public hospitals. Table 5 summarises the P&R characteristics of HE-ATMPs across a sample of EU Member States.

Cost-based pricing refers to a pricing strategy in which the price of a HE-product is determined primarily by its production costs. It is accompanied by cost-effectiveness analysis in Denmark and cost-effectiveness analysis, health and budget impact in Estonia.

Discussion

This paper analysed the Spanish standardized guideline used in pricing of non-industrial ATMPs approved to be administered under the HE and offers a review of different approaches being used in Europe to reimburse these therapies. Before engaging in the discussion around the pros and cons of each, we must highlight the very unique nature of price negotiations framed under the HE. We have seen that, with the exception of Germany, academic clinical groups dominate the HE landscape. Public and philanthropic funds fuel the research engines of these groups. Setting a fair price is key to offer both a fair compensation for the innovation produced to those that succeed in bringing their ATMPs from the bench to the bedside, who rely on the prices set for the reimbursement of their products to cover the costs associated with producing their ATMP and making it available to their patients at the right time. Hence, our analysis aims to bring clarity on the mechanisms used to set prices for ATMPs under the HE, and recommendations to set a fair and plain level fields that can foster a rich innovative ecosystem, fair compensation and incentives and reduce undue variability, for all those groups aiming to bring new ATMPs to their patients in situations where there is an identified unmet medical need to keep innovating.

To the authors knowledge, Spain is the only country that has published a guideline to support price calculations of non-industrial ATMPs. The guideline provides a detailed list of the different cost components to be included during P&R negotiations, but it does not specify the costing methodology to be used when estimating the price of each cost component. In this respect, ten Ham et al. (2020) have developed a framework to facilitate reporting costs that academic and other small-scale cell therapy manufacturers have to incur in [ 41 ]. The authors used activity-based costing approach to allocate costs to each item. They identified three steps (i.e., procurement, manufacturing and fill & finish), and defined four cost categories across them (i.e., materials, equipment, personnel and facility). Additionally, a distinction between fixed and variable costs was made within the categories. The study takes the developer perspective. Regarding costing items, the main difference between this framework and the Spanish guideline is that the former does not take into account preparation costs (known as medical costs in the framework), storage, nor transportation costs, while the later does. One of the interviewees advocated for the inclusion of preparation costs, because “the service offered encompasses not only the medication, but the entire procedure, i.e., selection of the patients, length of hospital stay during the aphaeresis, etc.)”. Regarding transportation costs, it should be noted that the Spanish guideline includes both the cost of transporting the intermediate and finished products [ 15 ]. It is important to keep in mind that the previously mentioned differences between the Spanish costing guideline and the costing framework developed by ten Ham et al. (2020) arise from the fact that the main objective of the latter was to develop a costing methodology, therefore, it reflects manufacturing costs instead of product price [ 41 ]. Therefore, it could serve as a guideline for informing price-setting in countries that employ cost-based or cost-plus approaches.

Innovation should be properly rewarded to promote improved quality of life, greater accessibility and affordability of systems [ 18 ]. In this sense, one of the interviewees raised a point about the size of the incentive to future research included in the Spanish costing guideline. This interviewee claimed that “the portion allocated to future research should be increased” and further states that “researchers may prioritise sustained research funding over merely recouping manufacturing costs”. For this reason, “with every unit sold, at least 30% should go toward future research to ensure that researcher can continues their work instead of just covering the costs”. In other words, despite this being an ecosystem primarily fuelled by public and philanthropic funding, it is still crucial to devise a thought system that offers sufficient incentives to research groups active in the HE-ATMP space to keep innovating. Nevertheless, a 30% incentive for academic developers could be perceived as posing a risk of unfair competition with the industry. In addition, a significant portion of the R&D for products developed under the HE is already funded with public money, which could make it difficult to justify such a high incentive from the perspective of the social legitimacy of public spending. Furthermore, it could trigger criticism regarding potential excessive profits in public institutions. However, the experts’ demand for a 30% incentive highlights a genuine need for sustainable research funding, the lack of structural resources to maintain ATMP production platforms, and the absence of specific mechanisms for economic return. This concern is closely related to the so-called “pay-twice” critique, which is particularly relevant to proposals to increase incentives for academic developers up to 30%. This critique emphasizes that the public bears the cost of drug development twice: first by funding early-stage R&D, and then by paying high prices once the therapy is approved [ 42 , 43 ]. While a higher incentive may help sustain translational research and cover operational risks, it intensifies concerns about duplicative public expenditure and challenges the social legitimacy of funding. Careful calibration is therefore needed to balance innovation incentives with public accountability and affordability.

Another interviewee stated that the increment of incentives up to 30% requires more careful consideration. Ex post, investigators often request additional research funding to pursue further developments if their projects succeed. The question arises as to whether such resources should be granted as a reward for successfully bringing a product to market, or whether the investment should instead be made available ex ante [ 44 ]. This issue becomes particularly salient when the funding streams originate from different sources, such as research budgets versus drug procurement budgets [ 45 ]. According to a recently published report on HE, progressive research incentives—exemplified by the Spanish model, whereby manufacturers may recuperate a proportion of their innovation-related expenditures—are instrumental in maintaining the infrastructural capacity required for ATMP manufacturing and in promoting greater transparency in pricing mechanisms [ 14 ]. One interviewee suggested that, in an HE environment dominated by public non-profit seeking developers, cost-plus pricing (that is, manufacturing (not development) costs plus a margin [ 46 ]) would be adequate. In such context, ex ante push incentives, through public research grants for instance to help researchers progress in early stages of development, and pull incentives that provide funding to sustain infrastructural capacity plus additional reward to groups that succeed in bringing their candidate to HE approval, through pricing mechanisms like the Spanish template with a percentage mark-up for incentives, can be complementary to meet a dual aim of maintaining existing HE therapies available to patients, and fostering groups to developing new ones that respond to other unmet medical needs.

Spain and Poland both employ a cost-plus methodology to determine the prices of advanced therapies developed under HE. In Spain, the applied margin is public and standardized through a graduated system ranging from 1% to 5%. In Poland, by contrast, one of our interviews helps us discover that the margin used by private developers is confidential, but it was not possible to ascertain whether this confidentiality also applies to public developers due to the absence of an official response. Moreover, in Poland, advanced therapies produced under the HE are not eligible for public reimbursement, which introduces an additional layer of opacity and limits external oversight of final pricing. In Spain, despite the existence of a standardized pricing framework, not all therapies are necessarily subject to it. A notable example is CEMTROCELL, developed by a private hospital, which is not required to comply with the official pricing guideline and therefore does not apply the graduated margin. This circumstance introduces heterogeneity within the Spanish system itself and illustrates that, although a transparent framework is in place, its application is not universal. With regard to transparency, the contrast between the two countries is substantial. The Spanish model, by publicly disclosing the margins and underlying criteria, tends to enhance public trust and reinforce the perceived legitimacy of pricing decisions, as it enables patients, clinicians, and other stakeholders to understand how final prices are derived. Nevertheless, such transparency may also be viewed as restrictive for developers, particularly private entities, which have reduced flexibility to align margins with their actual cost structures. Conversely, the confidentiality surrounding margins in Poland affords developers greater discretion, enabling them to apply or negotiate margins without external scrutiny. However, this opacity simultaneously results in lower public trust and reduced capacity to assess the appropriateness, efficiency, or equity of the prices established. In summary, while the Spanish approach to transparency strengthens confidence in the regulatory system, the Polish approach provides developers with greater flexibility but at the expense of diminished clarity and weaker public oversight. It should be noted that, in the context of HE-ATMP, reliance solely on a cost-plus model may be insufficient to adequately capture the clinical value of the therapy. The incorporation of value-based assessments, alongside adaptive payment mechanisms, could help reconcile the financial sustainability of the public system with the need to foster academic innovation [ 47 , 48 ].

Discrepancies were identified between the perspectives of interviewees and the recommendations found in the literature concerning the inclusion of publicly funded clinical trial costs. Some interviewees agreed that publicly funded clinical trial costs should not be included in the price of non-industrial ATMPs. An additional interviewee stated that even if a non-industrial ATMP was developed (almost entirely) with private funds, the cost of clinical trials performed before the authorization should not be included. Nonetheless, this interviewee agreed with the inclusion of the costs of the observational studies needed to keep gathering evidence for several years after the initial authorization (i.e., cost of pharmacovigilance). Another interviewee likewise advocates for the incorporation of long-term follow-up costs (particularly in gene therapies), as well as for other concomitant interventions, such as physiotherapy for products like NC1; neither of them is included in the Spanish costing guideline. With this regard, Ran et al. (2020) estimated cost of decentralized CAR-T production in an academic non-profit setting and they also excluded research and development costs [ 49 ]. Non-inclusion of publicly funded clinical trials in the price of non-industrial ATMPs might resolve the problem of the pay-twice critique, common for private sector owned innovations that receive public support. A framework that analyses the roles of the public sector as payer, regulator and investor in R&D of health technology [ 50 ], proposes that opportunity costs, such as R&D costs, compensation for the cost of capital, and sunk costs, should be included in price calculations of publicly owned therapies. Nonetheless, although no consensus has yet been reached among the scientific community concerning the inclusion or not of the publicly funded R&D in the price of medicines [ 43 ], the EU pharmaceutical directive does propose requiring marketing authorisation holders to disclose all public R&D funding received, aiming to boost transparency and support national pricing negotiations [ 51 ].

Strengths and limitations of different modes of reimbursement of non-industrial ATMPs

A major strength of the Spanish costing guideline is that it provides a comprehensive and detailed identification of the resources utilized. This is particularly valuable for estimating the cost of HE-ATMPs as these interventions frequently lack established provider reimbursement rates or DRG weights [ 52 ]. In other words, they often do not have clear routes to obtain a price or available pricing information. An important limitation of the Spanish costing guideline is that it does not provide any costing methodology to be used in cost estimation of each costing element included. Considering that inconsistencies in costing methods were found [ 53 ] -such as some healthcare organizations lacking advanced management accounting systems necessary to produce accurate and detailed cost estimates for individual services [ 54 ] or health economists in some cases not being well-acquainted with the specialized terminology of cost accounting- it is essential to use a standardized costing methodology to ensure that all relevant cost elements are included and estimated using the same approach, so that differences in the price of HE-ATMPs are not attributable to differences in costing methods. Additionally, direct manufacturing costs are only part of the factors that would influence the decision to reimburse. Therefore, what is important is the total cost of the therapy which may include in addition to starting material, collection and conditioning of the patient, the management of secondary effects, follow up obligations particularly in gene therapies and other concomitant interventions such as physiotherapy for products like NC1, but also all opportunity costs such as R&D costs, compensation for the cost of capital, and sunk costs. Other key limitation of the Spanish costing guideline is that it is not subjected to audits in the price-setting process. In this context, one of the interviewees explains that “now that we have more knowledge and more hospitals that are carrying out cell, gene and tissue-engineered therapies it would be desirable to have a small group of experts in HE-ATMP manufacturing process to validate in some way the costs that each non-industrial developer reports”. This interviewee adds that “the cost concepts reported in the guideline should also be reviewed, because the guideline was developed based on what was known in 2019, so there are some costing items that are (but should not be) missing, such as the viral vector”. In this regard, it is essential to emphasize that the inconsistencies identified between the transportation costs of the starting material, which one of the interviewees reported as absent in the guideline but are actually included, highlight the need for audits and further guidance for HE-ATMP developers to standardize the costs reimbursed to non-industrial advanced therapy developers. To the authors’ knowledge, the Spanish costing guideline is the only one of its kind. Nonetheless, an increasing number of countries are actively engaging in the development of HE-ATMPs. For example, the price of in-house CAR-T developed by the University Medical Center Groningen in the Netherlands is expected to cost € 80,000 per patient [ 21 ], but how this price was estimated is unknown. This could be (at least partially) clarified by the fact that there is currently no specific policy in place regarding the costing and pricing of ATMPs in The Netherlands -as explained by one of the interviewees-. Therefore, the normalization of cost components considered in P&R negotiations for non-industrial ATMPs may facilitate the development of a standardized European costing framework.

Only a few countries finance HE-ATMPs through DRG systems. They are designed for codified, standardized procedures; they assume a relatively homogenous patient populations and repeatable clinical pathways. However, the regulatory exemption for ATMPs is exceptional in nature, and individualized HE-ATMPS are often experimental or one-off treatments. Additionally, hospitals developing HE-ATMPS carry research, regulatory, and manufacturing infrastructure costs that are not covered by the treatment DRG. These innovation-driven costs need separate or supplementary funding mechanisms. Germany and the Netherlands are the main European examples where HE-ATMPs are financed through DRG systems, but they serve as an administrative channel, not as the pricing determinant. In practice, both of them use add-ons or negotiated payments [ 26 ], as DRGs alone don’t reflect true costs [ 55 ]. In Austria, where HE-ATMPs are also financed through DRGs, public hospitals depend on additional funding because DRGs do not necessarily cover total hospital costs [ 56 ]. However, clear structures for financing innovative therapies (including ATMPs) has not yet been established [ 26 , 57 ].

Strengths and limitations of the study

The major strength of this study is a first detailed analysis and discussion of the items included, and those not included, in the Spanish costing guideline. An analysis of this guideline (unique in Europe) is a novel contribution to the literature.

Our study has some limitations. First, data were gathered from a small number of expert interviews and questionnaires, which could introduce selection bias. The experts’ views may not be representative of all stakeholders involved in non-industrial ATMP pricing and reimbursement. Nonetheless, this limitation could be (partially) overcome by the selection of interviewees based on very different expertise. Second, many details of pricing dossiers and reimbursement decisions are confidential, limiting independent verification and transparency. Third, the regulatory and reimbursement frameworks for ATMPs -especially under the EMA pilot and HE clause- are still evolving. Therefore, findings will also continue to evolve as new policies are introduced and existing ones are clarified, offering opportunities for ongoing improvement.

Future research

Current research focuses on institutional and regulatory viewpoints. For this reason, explore how patients and healthcare professionals perceive the value, access, and ethical implications of academic ATMPs (i.e., incorporating end-user perspectives) would enrich understanding of societal impact and inform value-based pricing strategies. Additionally, it would be interesting to document and analyse case studies where academic ATMPs successfully navigated the HE pathway and received reimbursement. This in-depth analysis of real-world examples would help identify enablers, barriers, and lessons learned.

Conclusion

Spain has been a frontrunner with the development of their standardized form for price calculation of non-industrial ATMPs. However, while the Spanish costing guideline offers valuable detail for estimating the cost of HE-ATMPs, and a first example of its kind internationally, it lacks guidance on standardized methodologies for doing so, and audit mechanisms, leading to inconsistencies and limited transparency. Across the EU, approaches to HE-ATMP financing are heterogeneous. While Germany and the Netherlands apply DRG-based funding as an administrative channel, additional negotiated payments are necessary to cover true production and infrastructure costs. Other countries either apply regional reimbursement schemes (e.g., Denmark, Sweden) or lack formal pricing policies altogether. Establishing standardized European costing guideline could enhance the accuracy, comparability, and fairness of pricing HE-ATMPs across Member States. As a second-best scenario, or as an interim step towards European harmonization, clear, transparent and robust national pricing policies with standardized costing guidelines and audit mechanisms to avoid undue heterogeneity in prices for HE-ATMPs would offer a plane level field at national level and sufficient incentive for those innovating under the regulatory exemption to keep doing so.

Supplementary Information

Supplementary Material 1.

Supplementary Material 2.

Authors’ contributions

Conception and design of the study: ZS and JCR. Acquisition of data: ZS, JCR, JE. Analysis and interpretation of data: ZS. Drafting the article: ZS. All authors critically revised and approved final version of the article.

Funding

This study has received funding from the European Union’s Horizon Europe research and innovation programme under Grant agreement no. 101095593.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Competing interests

The authors declare no competing interests.

Footnotes

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Associated Data

Supplementary Materials

Supplementary Material 1.

Supplementary Material 2.

Data Availability Statement

No datasets were generated or analysed during the current study.