Optimal monitoring will depend on common reporting standards and the interoperability of the data systems with other initiatives that involve European collaboration across Health Authorities in Member States in particular with the medical devices regulation, the regulation on health technology assessment, the new mandate and roles of the ECDC and the EMA, the upcoming revision of the pharmaceutical legislation, and the European Health Data Space as well as the crisis preparedness and Recovery initiatives . While stand-alone monitoring is possible within the BTC-framework, it would be desirable to develop a joint monitoring and evaluation plan (with some/all of these initiatives) so as to capitalise on synergies and achieve cost-savings.

The data quality, processing and semantic interoperability have to be assured during the implementation (implementing acts as well as the development of the IT platform) in line with the Digital Europe principles. The feasibility study also establishes the technical and semantic interoperability with other legal frameworks and allowing re-use across these systems in line with the once only principle.

The monitoring will be possible thanks to the data from reporting obligations on Member States and SoHO entities. The SOHO-X data platform will enable the collection of all elements of the continuous monitoring plan as it automates the extraction of relevant indicators without additional input from stakeholders. It also provides an important perspective on the number of serious adverse reactions and events, which cannot be well interpreted in the absence of a denominator – the activity data. The platform also keeps track of the different pace of implementation across the EU. For the evaluation, additional data will be collected, in particular on the costs, the usability and the integration across systems. The data platform will be used to publish transparently aggregated indicators of general interest, such as SARE related to BTC, insufficiencies of supply or authorised processes. Some of these data collections will allow for synergies, such as cost savings for the annual reporting of SARE data (currently, an extensive annual exercise for the authorities and Commission).

-# indicators on the development of the data platform (e.g. connections of databases established, including more composite indicators on the resilience of the networks; registered entities)

-Clarity of regulatory pathways and comparable requirements for products of similar risk profile: # of questions answered at EU level on BTC (and of those, # of questions answered in coordination with pharma/MD initiatives

- Availability of technical standards that achieve a high level of safety and quality in a timely manner ; Data on activities and SARE available for decision-makers

Consistently used technical guidance on safety and quality that is based on the latest scientific evidence and available in a timely manner.

A series of monitoring parameters have been identified to evaluate impact of the proposed measures on each of the objectives:

E.g., annual reporting costs are estimated to go down from current EUR 5 000-15 000 to EUR 200-2 000 with an automated reporting tool.

The SOHO IT platform, financed by the Commission, will facilitate local administration including registration and reporting by professionals as well as authorisations and oversight by authorities.

Very high potential, given that every saving is multiplied by number of donations. Other examples could be the screening for tattoos/piercings or testing for syphilis.

Applicable for almost 1 000 imports per year of blood stem cells (from bone marrow or peripheral blood) through a central registry (World Marrow Donor Association registry, subject to one joint authorisation)

Recognition of authorisations of importing tissue establishments in other Member States, reduces need for ad-hoc import authorisations in different Member States

Model has rather assumed this to be a cost-neutral measure as the same number of resources (inspectors) allow for more oversight on most complex activities

Requests to authorise same new technologies are introduced and assessed in parallel across EU;

Graded oversight approach allows to oversee some establishments with lighter approach and less resources than today

The revision of the BTC legislation, with an approach proportionate to risks in different areas (authorisation or registration of establishments/entities, authorisation of new preparation processes, health monitoring of certain donors and offspring ) also brings opportunities for savings in the sector, and for carrying out some activities more efficiently within the same resources (e.g. risk-based inspections), though these opportunities have not always been fully quantified. The table below gives an overview of the main opportunities under the preferred option. Several of these do address some of the undue burdens flagged under section 2.

For the protection of donors and offspring, donor registries will play a key role, while complying with the GDPR. EU-level donor registries will, for instance, allow centres to apply agreed maximum numbers of donations by a single donor . In the workshops organised as part of the impact assessment, there was a consensus on the need for donor follow-up proportionate to the level of intervention or risk associated with the donation. A registry for children born from MAR was discussed but the efforts this would require were not seen to be justified considering its limited expected benefit to individual children and the potentially misleading association it might foster between certain conditions and children born from MAR .

It should be noted that some stakeholders, through the consultation process, asked for specific legal frameworks for certain particular substances (plasma, cord blood , FMT , human milk , allogeneic bone grafts), arguing that the specificities of those substances require a ‘separate’ legal framework (for example, an implementing act of the basic act). Two stakeholder organisations also expressed that the Blood and the Tissues and Cells Directives should remain separate. By setting strong common principles to protect citizens and then making reference to technical standards of expert bodies for technical rules, it is possible to respect the specificities of these different substances within one single new act covering all SoHO. These specificities will be recognised in these technical standards, and the proposed risk-based approach to oversight allows all of the SoHO ‘sub-sectors’ to be regulated appropriately without increasing complexity or time needed for implementation. For example, for breast milk and FMT, the legal act will bring them within the scope of this legislation while the substance-specific technical standards of the expert bodies , will take into account the specificities of those substances. For plasma, introducing better definitions in the legal act, to reflect the intended use (transfusion or manufacturing of PDMP), can allow for further specifications at technical level by expert bodies, and address concerns raised regarding undue burdens (see section 2.1.6).

The choice of legal instrument, a Regulation instead of Directives, will minimise divergence due to national transpositions and interpretations. In any case, Member States have the right, as set out in Article 168(4)(a) of the TFEU, to set more stringent standards, which might for example be required to fit to national healthcare settings. This proposal will respect this but will bring more transparency on such more stringent national standards in order to facilitate cross-border exchange and optimal access to BTC for patients across the EU.

The conclusion of the IA is that the optimal approach to setting technical standards is to establish a ‘hierarchy of standards’ approach in the legal drafting, a concept which emerged from the IA process. The legislative proposal will therefore be based on option 2, with joint requirements for technical standards and guidance developed by the EDQM/ECDC, but still with the possibility to have fully centralised requirements (option 3) in a limited number of cases where considered necessary, and with the possibility for local/decentralised requirements where these are not developed under options 2 nor 3 . This ‘hierarchy of standards’ will only apply on the technical elements, other elements (like principles) will still be set in EU law.

In the legislative proposal, an efficient implementation, adding flexibility and proportionality, will be followed. All stakeholder consultation activities showed a broad support in general for option 2 to define the technical standards and guidance, although the need to ensure that higher level principles on safety, quality and efficacy are defined in EU legislation was also highlighted. However, it was pointed out that, to be successful, appropriate representation in the drafting of technical standards by expert bodies will need to be ensured, including EU Member States’ authorities, professionals from the BTC sub-sectors , and industry, to ensure transparent and evidence-based working methods . Those concerns can be addressed through agreements between the Commission and those expert bodies.

Finally, an equity analysis has been performed too. This analysis starts from a social impact matrix in which the position of the various stakeholders towards the set of policy options being considered is summarised using qualitative scores. Based on this, SOCRATES then generates the following information: 1) indications of the distance between the positions of the various social groups; 2) ranking of the policy options according to actors’ impacts or preferences; 3) vetoed options, the main idea here being that it is not prudent to implement policy options which would create too high a degree of conflict (and thus the decision taken might be very vulnerable). The SOCRATES equity analysis shows that option 2 is also the least conflictual option, as no stakeholder is against its implementation. This is not true for any of the other options considered. All the data and technical details on the results summarised here can be found in Annex 4.

The Feasibility study identified the single digital system (measure M6C) as the most efficient approach (Annex 19) – digitalisation is the only area where a centralised solution scored the best on the criteria. The requirements for the set-up of the SoHO-X platform are currently being defined by the Feasibility study. To allow re-use of data, federated networks was identified as the most efficient approach (by copying and mirroring data they reap the benefits of sharing and analysing data – while allowing the data to remain local in existing structures and ownerships.). As all three sub-options for digital implementation are horizontal, this digital architecture is compatible with the overall preferred option 2.

Finally, since we have computed the rankings according to the equal criterion weighting assumption, we then looked at what happens if all possible combinations of criterion weights are considered. This exercise is carried out by means of a global sensitivity analysis. The results are very stable: in fact, whatever weight set we use, option 2 is always the top-ranked option.

To test the robustness of results a sensitivity analysis was performed. We looked first at the influence of the exclusion of the various criteria and dimensions, one at a time, and at the effect of using the subset of criteria belonging to one dimension only (i.e. first one criterion at a time is eliminated and the corresponding ranking is obtained, later a whole dimension with all its criteria is eliminated and the effect on the final ranking is checked). Proceeding in this way, it became clearer and clearer that option 2 is the most desirable, in fact it occupies the first position in 93 per cent of all the rankings obtained.

The comparative assessment of options based on the SOCRATES tool using an equal weight of all the criteria resulted in the following ranking: Option 2 is the best choice followed by option 3. The set composed by option 1 and the baseline is clearly the worst (see figure 4.5 Annex 4).

The proposed legal basis (Article 168(4) of the TFEU) allows Member States to maintain and introduce more stringent measures when they consider them necessary. The proposal does not interfere with that right but does increase the level of safety and quality to be achieved in all Member States, thus reducing the need in most cases for more stringent measures that can create barriers to exchange and to patient access. In addition, the proposal will ensure the adoption of more stringent measures is made more visible so that exchanges can be more easily organised in full respect of those measures. Given that rules relating to ethical aspects of this field, or to healthcare organisation, are not included in the proposal, no special circumstances in individual Member States were identified that required a particular territorial variation in the measures to be applied.

The proposal balances the need for clear and high standards to protect donors and patients equally while ensuring that Member State competences for health care organisation are not compromised. To achieve this need, the two current basic Directives will be replaced by a Regulation and the existing implementing legislation will also be repealed. This instrument will provide a significantly higher level of clarity and conformity to common safety and quality principles.

-Similarly, although the proposal includes new requirements for demonstrating efficacy for novel ways of processing or using BTC, these requirements are graded according to the degree of risk or novelty and the most demanding clinical studies will be required only for those (rare, less than 5%) novel processes that imply higher risk for patients.

-Furthermore, planning of inspections will be adapted to the inherent risk of the establishments, allowing for more frequent inspections for those with high volumes, complex activities or with a poor safety-record.

-Although the scope of the proposal will affect operators and activities not previously within the scope of the BTC framework, a graded approach to oversight has been defined, with lighter requirements for registration only or for preparation process authorisation only for those entities carrying out BTC activities with lower risk levels. Some entities previously inspected and authorised as BTC establishments can be moved to a simpler registration regime with limited reporting requirements.

The principle of proportionality is strongly reflected also in the new provisions for oversight of operators working on BTC.

The measures proposed are limited to actions that need to be taken at EU level in order to reach the objectives, in an effective, efficient and coherent manner. The overall initiative is limited to aspects that Member States cannot achieve satisfactorily on their own, and where there is an EU added value. For example, very few Member States can harness significant and wide-ranging expertise for every technical aspect of ensuring the safety and quality of BTC for donors and patients in their own Member State. The added value of the EU approach in this proposal is to ensure access to a high level of scientific and technical expertise. However, the analysis also shows that a fully centralised system does not perform better and that the most proportionate solution is to rely on expertise already available in the ECDC and the EDQM (Option 2).

The policy options are not different in terms of coherence with the food framework. Including breast milk banks in the scope of the BTC framework would not have an impact on EU food legislation. When breast milk is used as a starting material for the manufacture of breast milk fortifiers placed on the market. Under that framework, the BTC framework would apply to the donation, testing and collection steps and Food legislation would apply for subsequent steps.

Strategic alignment on digital transformation, the integrity and resilience of our data infrastructure, networks and communications. Respect of personal data and fundamental rights. The SoHO-X initiative is also aligned to on-going work in the frame of the Regulatory Reporting Community on interoperability and on re-using existing digital components (such as eIDAS REGULATION (EU) No 910/2014 or the regulation proposal for a European Digital Identity). It follows clear principles set out in ongoing EU digital initiatives and digital principles (including the European Strategy for data and the Data Governance Act). It enhances the ‘once-only’ principle as stated in the REGULATION (EU) 2018/1724 of a Single Digital Gateway.

The proposed structure is fully aligned to the proposed European Health Dataspace (EHDS), and the SoHO-X Platform is considered to be a domain-specific use case (node) in EHDS. It is designed to facilitate exchanges and reuse of data with adjacent legal frameworks. Protection of citizens’ health data; developing a federated, networked data system based on technical and semantic interoperability and the FAIR principles. The BTC sector can be seen as one domain – the central data system being a node in the EHDS network.

Facilitated and reliable availability of blood units for transfusion during cancer care, of units of bone marrow transplants for blood cancer patients, and of fertility preservation for cancer patients.

Option 2 would bring more coherence with the ECDC proposed strengthened mandate, which is planning to further expand the role and tasks of the ECDC regarding epidemiological diseases/risks in substances of human origin. Therefore, option 2 would allow further synergies with the ECDC tasks.

Strategic alignment on crisis preparedness; improving available data to manage crises; coordination mechanisms, improving resilience of supply to life-saving treatments. The European Health Emergency Preparedness and Response Authority (HERA) can play a role for such crisis preparedness measures in the BTC sector, once HERA is fully deployed.

Improved supply of plasma for manufacturing PDMP is a key element to ensure supply continuity of these therapies (also subject to the structured dialogue and to a BTC/Blood Working Party collaboration).

The BTC advisory mechanism will allow, regardless the delineation, to improve regulatory coherence by clarifying appropriate safety and quality rules and oversight at the borderline. This is in particular important where the classification of BTC is unclear, where BTC become starting materials for medicinal products (PDMP and ATMP) or where BTC are combined with products under the MP (or MD) framework.

The delineation between the BTC and pharma sectors, set by definitions in the pharma framework, will not be altered by the BTC revision. (However possible developments might occur under the pharma revision, which will have to be assessed there for their impact on BTC and will be closely followed and coordinated with).

Strategic alignment on access, safety and quality, resilience of supply, autonomy and innovation. The EDQM as expert body under option 2 plays a (similar) technical role in the pharmaceutical framework (Pharmacopeia).

The BTC advisory mechanism will allow, regardless the delineation, to improve regulatory coherence by clarifying appropriate safety and quality rules and oversight at the borderline. This is in particular important where the classification of BTC is unclear, where BTC become starting materials for medicinal products MD or where BTC are combined with products under the MP (or MD) framework.

A BTC advisory mechanism will facilitate coordination with the MD sector, in particular to correspond to its working group on classification, its procedure to authorise combination products (MD/BTC) and the provision for the Commission to coordinate different sector authorities at EU level.

Strategic alignment on safety and quality. The two sectors are alike in their diversity and innovation dynamics: both frameworks use a risk-based approach to define proportionate requirements on safety, quality and efficacy (performances in the MD sector). Similar structure of ad hoc working groups. Technical integration on standards, nomenclature, interoperability with EUDAMED. – No impact of policy options.

Provisions for vigilance reporting can be more aligned, and closer collaboration can be planned between organ and BTC competent authorities (for cases of donation of tissues and cells, and organs, by the same donors). The intensified use of expert bodies like the ECDC and the EDQM (option 2) can also be of benefit for the EU organs legal framework.

The policy options mainly relate to technical aspects within the BTC sector, and therefore make little difference in terms of coherence with most initiatives outside the BTC sector. Nevertheless, some important elements of coherence need to be mentioned with the following EU priorities and initiatives:

Not all saving effects from digitalisation have been quantified in this comparison, but it can be expected that the policy options that allow for more harmonized regulation (joint under option2 and centralised under option 3) will allow to capture these benefits better. Besides the benefits on monitoring/reporting for professionals (see above), digitalisation efforts will in particular allow to build a shared digital space for the SoHO sector, to support the use of best available evidence and data from the professionals, health providers (including innovators) towards and between public authorities and other stakeholders (M3B and M4A).

Option 3 entails higher costs for the EU budget (NPV: EUR 6.9 m for option 2 and EUR 8.4 m for option 3). Given the better benefit and impact profile of option 2 and the lower costs for EU budget, option 2 is the most efficient option.

EU level investments to support development of technical standards, oversight, coordination as well as a data platform to exchange data flows in the sector can facilitate uptake by the sector and thus be a key success factor.

It needs to be noted that the baseline values are zero for the new measures. Moreover, the calculations do not take into consideration the cost of all activities in the sector (e.g. the cost of tests or processing required by the technical guidance; or the costs of the internal accounting and supply management systems – such costs could not be retrieved in the public settings of most BE/TEs). Comparisons to the baseline should take this into account, and might rather consider a comparison to the overall sector value which is around EUR 8-12 b (see Annex 8, Table 8.3). An implementation cost of EUR 32.2 m for the sector corresponds to 0.3-0.4% of this sector value.

Options 2 and 3 are estimated to add significantly less cost for the sector (EUR 32.2 m). The costs of options 2 and 3 are similar for the sector. The main costs are driven by the monitoring and reporting costs - for (hospital) entities processing BTC (M1A), for establishments monitoring certain categories of donor and offspring born from donated BTC (M2A), and for establishments monitoring critical BTC supplies (M5A). However, due to initial one-off costs for digitalisation, the annual administrative costs can remain rather limited per entity/establishment – below EUR 500 to report BTC processing in hospital/entity (M1A), just above EUR 5000 to monitor donors/offspring (M2A) and around EUR 1250 for monitoring supplies (M5A).

The cost calculation shows that compared to the baseline, option 1 increases the annual costs for the sector by EUR 45 m – a significant change, considering the size and largely public nature of the sector. This would disproportionately affect establishments that are smaller in size and have not yet implemented the proposed measures. Considering that option 1 underperformed in terms of the benefits compared to option 2 and option 3, this is clearly a suboptimal option.

Efficiency considers the extent to which the options incur costs and other resource implications for the sector, National Competent Authorities, the EU and other stakeholders. It also takes into account the allocation of the costs across the actors: one-off and compliance costs for NCAs and BE/TE with particular attention to the smaller organisations.

The common measures to improve resilience of the BTC sector (objective 5) are expected to improve crisis preparedness by ensuring that supply can be monitored and possible interruptions can be prevented by early action.

The three options foresee different technical solutions for assessing the risks of novel processes, where the use of expert bodies is expected to be most efficient (option 2). Measures to facilitate the development of safe and effective innovative BTC therapies were assessed in relation to criteria of how best to assess safety, quality and efficacy of those therapies across the EU, impact on R&D (open innovation, transparency), as well as what are the impacts on finances (affordability) and patients’ access: options 2 3 score higher than option 1, due to their possibility to have harmonised rules for the assessment of novel preparation processes will be more efficient (possibility for Member States to refer to an authorisation already given, so less data needs to be collected and provided by an establishment requesting for the authorisation).

The common measures to facilitate innovation (objective 4) are synergistic in providing a clear regulatory pathway for innovators - one that allows public and private health providers, academia, as well as industrial manufacturers (using BTC as starting materials) to develop innovations under clear and transparent provisions.

All common measures to strengthen national oversight systems (objective 3) are expected to reduce barriers to exchange of BTC across the EU. Measures setting principles and guidelines are necessary first steps to achieve transparency and convergence. Further measures, mainly at EU level, support Member States in the consistent implementation of inspections by improving the capacity of Member States to inspect, and through measures to facilitate cooperation and trust between them (EU audit, joint inspections…). Still, option 1 with possibly more divergence in the practices of establishments would mean more need for oversight work and more difficulties to oversee the sector for the NCAs, where option 2, and option 3, would be more effective.

For donor and offspring protection (objective 2), the same criteria of time needed for update, quality and consistency among Member States of safety and quality rules were used. The scoring of the options is the same as for objective 1.

The common measures for objective 1 were also considered, in particular the possibility of filling legal gaps and ensure safety and quality for currently unregulated therapies.

For patient protection (objective 1), options were assessed in relation to the time needed to update the rules for safety and quality, the quality of the rules and their consistency among Member States. Option 2 performed best on these criteria, followed by option 3 and then option 1 (with option 1, the timing for update can be short for those establishments having sufficient capacity for conducting risk assessments of their procedures, but this will be cumbersome for small establishments; in addition, this could lead to more divergence among Member States, and even within Member States. With option 3 the consistency can be higher but the timelines are significantly longer to come to updated safety and quality rules).

The performance of the three options on the various dimensions is summarised below. The multi-criteria decision analysis shows a clear ranking: option 2 is the best choice followed by option 3. The set composed by options 1 and the baseline is clearly the worst one. More information can be obtained by checking the pairwise comparisons, which allow one to be fully aware of the mutual weaknesses and strengths on each single evaluation criterion. This information is summarised graphically in the figures (pairwise comparison) in Annex 4, which illustrates the degrees of credibility with which any option is preferred or indifferent with respect to another one on each single criterion. From these figures it is possible to deduce that options 2 and 3 are indeed very similar, although there is a distinct stakeholder preference towards option 2. In fact, if one looks at the performance on each of the single criteria, it is possible to see immediately that only the digital criteria are slightly in favour of option 3, while all the other criteria evaluate these two options as indifferent or are strongly in favour of option 2. On the contrary, when comparing one of these two top options with the other options the preference relation is very clear.

The impacts were assessed against the baseline for each of the policy options (the common measures are part of all policy options).

The identified impacts of the proposed policy measures were subjected to a multi-criteria decision analysis to compare the effectiveness and efficiency of the options. To that end, this IA has piloted the tool of the JRC called SOCRATES (SOcial multi-CRiteria AssessmenT of European policieS – see Annex 4), using it to compare the different options based on the criteria described in the previous section. SOCRATES applies a mathematical aggregation rule to the information collected during the assessment and compiled in the impact matrix (Table 4.1, Annex 4).

Research and consultations did not provide any information suggesting that the options would result in any specific and significant changes to natural resource use or environmental impacts. In particular, no changes in processing, no increase in waste or pollution is expected as a consequence of any of the policy options.

Strengthening the fundamental rights of donors. Non-commercialisation of the human body. Donors should not pay for any costs associated with donations, nor be remunerated for their donations (Charter of Human Rights, article 3)

Consistent application of privacy provisions for personal data in the BTC framework. Offering secure infrastructure, technical assistance and GDPR advice will ensure that this data is secure and GDPR provisions are respected to ensure the protection of personal data (Charter of Human rights article 5)

Revising discriminatory terms and provisions (e.g. consistency in the term 'partner'; deferral from donation must be proportionate to risk) (Charter of Human rights article 21)

The measures that touch on some fundamental rights are the same across the three options (common elements); they are expected to have a positive impact (see Table 6). Though it needs to be underlined that most ethical points, in particular the ones related to access and organisation of healthcare, as well as the rights of children born from MAR (e.g. right to know their origin), are decisions taken by Member States at national level. The specific aspects of fundamental rights protection addressed are summarised in the table below, and cover reducing discrimination, privacy and non-commercialisation of the human body. In a workshop on ethical issues , most participants expressed agreement with the introduction of donor protection rules. While the general principles in legislation are the same across the three policy options, stakeholders had more confidence that option 2 and option 3 would improve fundamental rights, due to the stronger cooperation of experts.

An overall EU budget of more than EUR 8 m is being foreseen to allow for the development of a federated SoHO-X platform to support the national authorities and (mainly public) professionals in the BTC sector.

A further developed single system for information management, in compliance with the General Data Protection Regulation (GDPR), has however important benefits in terms of flexibility, security and possibility for evolution. Such a system can host flexible solutions, allowing Member States and BE/TEs to maintain and connect with their own system or re-use existing components, through more secure (than currently) GDPR-compliant systems (federated approach). A single system on a European scale can exponentially increase the value of data and reduce certain costs (e.g. security, recurrent reporting). Such solutions would ensure the feasibility, accessibility, interoperability, and reuse of digital assets (FAIR principles), and could be used with the main European and global data standards and other initiatives. It could become an important node in the European Health Data Space and more broadly the EU digital ecosystem: in this case the work of sector experts is essential for the high quality, consistency, availability and use of data.

Cross-border exchanges are important to match each patient to the best possible BTC graft (unit). Improving harmonisation (horizontal measures on oversight and consistent technical requirements in policy options 2 and 3), and increasing transparency where national more stringent measures are in place, will eventually reduce variations in national rules that create barriers to the exchange of BTC among Member States.

Several cases have been reported in the UK and Switzerland, where strengthening frameworks for hospital prepared therapies make it possible to offer more affordable therapies and to attract patients from abroad (EU) . A stronger EU framework can allow EU centres of excellence to treat EU patients as well as non-EU patients with high quality therapies .

The improved environment for (open) innovation and research could strengthen the EU’s competitiveness as a global location for research and innovation in BTC vis-a-vis third countries.

SoHO are not regulated under an internal market (Article 114 TFEU) legal basis, as described in sections 1 and 3. Beyond the facilitation of BTC supply within the EU, and the possible effect on the need for imports from 3rd countries (e.g., plasma), there is little direct evidence on the impact of the policy options on trade and competitiveness.

As eventual outcome, BTC therapies have the potential to fully restore health of citizens, and transform them from seriously ill patients (blood cancer, burn-wounds, and blindness) into active citizens.

Some increased needs for employment of digital staff can be expected, given the digital dimension of the proposal.

The impacts of the measures on employment were not quantified. But a streamlined, reliable and proportionate legal framework will increase the possibility to bring therapies with added value to patients. It allows growth in certain sub-sectors, e.g. the sub-sector of MAR, which is continuously expanding to address increasing societal needs.

These savings for public health can be expected regardless of the policy option.

Fourth, public health research savings can be made from the possibility to have risk-based, proportionate evidence collection for the authorisation of BTC processed or used in new ways (M4B). Not all new therapies need full clinical trials; the evidence generation for incremental changes (e.g. changes in the packaging, adjustments in the testing) remains proportionate to the risks . Where clinical trials would typically cost up to EUR 600 000 in the BTC sector, evidence for innovations with a medium level of risk could be collected through a clinical follow-up plan and be limited to EUR 60 000 and to EUR 25 000 for low levels of risk.

Thirdly, there are opportunities for healthcare cost savings by correcting requirements faster when safety and quality measures become obsolete (M1B and M2B). Across all policy options, technical requirements for testing and processing would reflect the best available evidence; no outdated tests/procedures, nor those of unproven value, would be authorised. This will impact BTC supply in two ways: as well as reducing costs, it will also mean fewer deferred donors and less discarded BTC .

The new authorisation and data reporting processes will also improve availability of better evidence/data for national/local decision-making to ensure the effective use of BTC. This evidence may also be used in settings that go beyond overseeing safety and quality: not only for treatment protocols and guidelines; but also for pricing and procurement of technologies/services for health providers or even in more formalised health technology assessment processes (i.e. helping to identify the most cost-effective BTC), helping national budget holders in their pricing and reimbursement decisions and also in the conditions and rationalisation for use of BTC therapies. A good example is the study and use of convalescent plasma for the treatment of COVID-19 ,.

Firstly, there is a broader digital impact (see section 6.4) which will bring administrative efficiency for actors and authorities.

The common measures are foreseen to impact positively the sustainability of healthcare budgets that go beyond the administrative efficiencies described above (which principally impact publicly funded authorities and also publicly funded BE/TEs).

Of note, apart from the requirements for the novel preparation processes risk assessments (defined by BE/TEs, or by expert bodies, or set in EU law according to the policy option), the measures on innovation are common across the options and therefore the three options score equally.

Impact on innovation in the BTC sector: extent to which measure facilitates R&D (fostering partnerships across the public and private sector; transparency of research: circulation of data, research results or researchers; transparency of R+D costs)

Regulatory coherence: the extent to which there are consistent/comparable regulatory requirements for BTC, including coherence across legal frameworks (BTC, pharma, med tech)

Regulatory coherence: the extent to which there is clarity as to the regulatory framework to which the substance/product belongs (including for products that move from one framework to the other and currently unregulated products)

In addition, measures to fill legal gaps (M1A) for SoHO not currently regulated under the BTC framework and those BTC processes carried out in surgery or next to the patient (bedside) will extend these positive impacts on legal clarity and facilitation of innovation also to those therapies that previously were unregulated. This benefit will be enhanced by the provision of a data sharing platform at EU level.

In addition, such an EU-level mechanism should interact and coordinate decisions with equivalent mechanisms in adjacent legal frameworks . This cross-sectoral collaboration will improve the cross-sector consistency of advice on regulatory requirements and will also provide a much-needed channel of effective communication for agreeing on technical requirements when BTC are the starting materials for products subsequently manufactured under pharmaceutical or medical device frameworks or when BTC are combined with medical devices or medicinal products before human application . Such EU-level coordination amongst sector-authorities will for example allow to develop an approach to facilitate import of BTC that are starting materials for ATMP, one of the undue burdens that was flagged (section 2.1.6). It will however be important to ensure efficient mechanisms of coordination as expressed by some important actors .These aspects are further elaborated in Annex 12.

An advisory mechanism on the application of the BTC legal requirements (M4A) is expected to facilitate innovation by increasing legal clarity and consistent advice to BTC developers and authorities across the EU (regulatory coherence) . Such an advisory mechanism would help clarify EU-level regulatory pathways for BTC innovation across public and private sectors, and the transparency brought by publication of its advice is expected to facilitate the development and supply of newly developed BTC. In particular, improved clarity would create an environment in which public sector (and academic) BE/TE would be more prepared to invest in the development of innovative BTC treatments and organise for more local (diversified) supply - thus further improving patient access to innovation (see also section 6.2). No fees for applicants are foreseen.

Supporting innovation, with proportionate requirements, is particularly effective in this sector, as results are generally published and circulated openly so that many BTC establishments can implement improved processes once they have been developed and authorised in one establishment (third criterion in Table 5). The availability of a data-sharing platform for developers and authorities will allow for further sharing and leveraging of data, in line with existing practice of open innovation and partnerships applied by the public academia and professional societies , as well as with European Research Policy. This improved transparency of research data will not only increase regulatory efficiency, it will also allow professionals to provide patients across the EU with wide and fast access to the BTC that are processed or used in new ways and are shown to be safe and effective.

The proposed risk-based approach to authorising changes in BTC preparations or use (M4B) offers an opportunity to enhance efficiency and balance safety and access by ensuring sufficient levels of safety and quality for BTC with lighter oversight requirements when justified by a low level of risk or novelty. In most cases, with negligible risks, current safety monitoring requirement might be considered sufficient. However, where high risks are identified, or the process is particularly novel, the requirements for demonstration of safety and efficacy in the patient would be more coherent and comparable to those applied in other frameworks, like to authorize pharmaceuticals, requiring clinical comparative studies. As well as scoring well against the criteria of improving process authorisations and facilitating innovation in the public sector where these developments normally occur, the measure also contributes to cross-sector consistency and coherence. This is therefore considered a key element needed to ensure that patients can access safe therapies of proven benefit (for access benefits see also section 6.2). There is broad support that such legal requirements should be introduced in EU legislation for demonstrating safety, quality and efficacy when BTC is prepared or used in new ways .

Two measures (M4A and M4B) are proposed to facilitate innovation by defining a clear and proportionate regulatory pathway that is tailored to the actors (mainly public sector bodies) in the BTC sector. The impact of these measures is assessed against 5 criteria, in comparison to the baseline (Table 5).

In order to facilitate implementation of the different measures across the five objectives, some EU support measures are suggested to offset costs for authorities, establishments, entities and clinical societies during initial adjustment (around EUR 24 m) and later during the implementation phase (EUR 6 m per year) (see Annex 17 for more details).

It needs to be noted that the investment in common guidance under option 2 (and 3) still brings a significant one-off cost for the establishments (EUR 11.7 m) but then allows for an annual administrative saving of EUR 0.5 m compared to the baseline. This saving is not possible under option 1.

-Under options 2 and 3, establishments can rely on central standards for their crisis preparedness plans. This is expected to significantly reduce effort on the set-up costs – which is particularly significant for smaller establishments. Calculations therefore show overall costs for establishments to be limited to EUR 0.7 m, while a cost of EUR 0.3 m will be incurred by authorities to verify preparedness plans in the establishments. The cost of EU coordination and to prepare common guidance is EUR 0.3 m under option 2 and EUR 0.4 m under option 3.

-In option 1, the establishments are to define individual crisis preparedness plans. The absence of a central standard makes it difficult to rely on common ICT solutions; and it is also estimated that it will require a lot of time for the set-up and revision of preparedness plans. These measures bring a significant extra cost of EUR 7.0 m for establishments, partly due to the need for each of them to bring in expertise. Costs for Competent Authorities to evaluate the crisis preparedness plans are estimated at EUR 0.3 m. The cost for EU coordination is EUR 0.2 m.

The requirement of preparedness plans (M5B) for all BE/TEs, which will then allow to respond when shortages are notified, is also subject to policy options.

It needs to be noted that the costs for establishments includes a high one-off cost to invest in digitalisation (EUR 16.6 m in options 2 and 3), which then allows a significant reduction in annual administrative costs to monitor and report shortages (EUR 3.1 m, or less than EUR 1 300 per establishment supplying critical BTC).

-Under options 2 and 3 the cost for the 2 500 concerned establishments is reduced to EUR 4.2 m, with a similar low cost of EUR 0.1 m for the authorities. The cost for EU coordination, including IT support, and updated guidance is EUR 0.8 m EUR under a joint regulation policy option (option 2), and increases to EUR 0.9 m under a fully centralised policy option (option 3).

-Under option 1, in absence of common guidance, the cost for the 2 500 concerned establishments is EUR 6.5 m. The cost for authorities of EUR 0.1 m is relatively low as they are only expected to be involved in rather few occasions when sudden supply shortages are notified. There is also a support cost at EU level of about EUR 0.7 m for coordination, including IT support.

The introduction of supply monitoring and notification rules (M5A) is applicable on establishments whose supplies are considered critical for the patient safety and impact . This measure is expected to subject to the policy options:

The new BTC legal advisory committee (M4A), including members of national BTC authorities, can be run efficiently through online exchanges and meetings, with support from EU staff (secretariat and organisation of regular physical meetings). This committee can also meet with equivalent committees and groups in other EU legal frameworks (e.g., Committee on Advanced Therapies in EMA). The overall costs for these committee meetings and time of expert staff in national authorities is estimated to be EUR 0.5 m, and is a cost counted for the EU (considering 7 meetings per year and additional 3 meetings with other sector authorities ).

An important consideration that is not included in the calculations here is the potential saving on the 19 Member States with an established baseline for healthcare providers and authorities. This can bring a significant potential for savings (see section 8) for those countries with existing practices (70%), thanks to the sharing of data, assessments and collaboration for identical processes, allowing to reduce the duplication of effort across different Member States. Experience from other fields shows that smaller Member States can particularly benefit from reusing this information . While we followed a conservative estimate here, it might be argued that, at EU level, such savings would offset the costs for healthcare providers and authorities.

Eventual calculations estimate the cost for healthcare providers (collecting clinical evidence) to be around EUR 3.6 m and for authorities around EUR 0.8 m. Costs for providers and authorities will be a bit higher under option 1 – where they cannot rely on common guidance. The EU will bear costs of about EUR 1.0 m for IT, support and coordination, as well as for developing common technical guidance. The latter part will be EUR 0.2 m more expensive in case of stand-alone development (option 3), and EUR 0.2 m lower in case of no development of common guidance (option 1) vs joint development (option 2). These costs fall mainly on 8 Member States without an established approach for assessing such innovations.

The introduction of a risk-based authorisation mechanism for changes in BTC preparations and use (M4B) will require the proportionate collection and assessment of clinical evidence on safety and efficacy. Sensitivity analysis shows that these costs vary radically based on the extent of data collection (adverse occurrence reporting can be organised for EUR 500, but clinical investigations, clinical evaluations or clinical trials are more costly, potentially going up to EUR 15 000 - 75 000), driven by the number of patients, as well as the number of data to be recorded (see Annex 12). These costs of data collection on outcomes of patients in the clinic can be a heavy burden on the BTC sector. However, where real world data registries and electronic health records of the hospitals can be used for such (secondary) decision-making by NCAs, the reporting costs would radically drop, underlining that digital health investments can be leveraged. Allowing for the wider use of clinical trials, for high-risk innovations, by national BTC authorities can be considered as an efficient way to ensure safety and efficacy of high risk BTC preparations. In several countries these BTC authorities are already using clinical trials, and in many countries the same as the authorities in charge of pharmaceuticals.

Furthermore, the NCAs will also be able to organise joint inspections, bringing in colleagues from other Member States, for example to inspect an establishment using a rare technology. These are estimated to cost authorities about EUR 0.1 m and the EU about EUR 0.5 m, in order to fund extra time for staff, travel and translations. The organisation of EU audits on national oversight systems would cost the EU around EUR 0.5 m.

The introduction of principles and new measures for oversight (M3A) entails several elements. Oversight principles (e.g., the need for independency and adequately skilled staff) are expected to bring an extra organisational cost for half of the authorities (EUR 0.5 m). The risk-based scheduling of inspections, to replace the fixed-frequency inspection rule that was flagged as bringing an undue burden (section 2.1.6) is expected to be cost-neutral, as modelling confirmed that it is possible to inspect all establishments with adapted frequencies of high, medium and low complexity inspections with the same number of person-months as required for the current regime of standard inspections every second year. This will significantly increase efficiency of oversight.

All measures explored here are horizontal, and do not differ per policy option. This objective will require efforts both for the national authorities that oversee the sector and for the EU to support these authorities.

-Options 2 and 3: When these establishments can directly implement technical rules prepared centrally (option 3) or jointly (option 2) this cost (person-days) remains limited for establishments to EUR 4.1 m. There is also a verification cost for authorities (during inspections) though for implementation only (0.2 m). There is an extra cost for the EU for coordination to develop technical standards, which us higher if rules are prepared centrally (EUR 0.9 m for option 3) than jointly (EUR 0.5 m for option 2).

-Option 1: it will be more expensive for 2 350 establishments working with donors and 1 770 working with MAR to identify appropriate technical rules for their local setting/activities, and then implement them (EUR 5.1 m) – the costs of this requirement may be difficult to cover for smaller establishments . This option will also entail extra costs for the NCAs to inspect whether these technical rules are appropriate for the local setting, and well implemented (EUR 0.5 m). Like for objective 1, EU costs will be limited to EUR 0.1 m for coordination support.

The three policy options have been explored to provide for up-to-date technical rules for safety and quality of donors and offspring (M2B) and estimated to bring following costs:

To include the protection of donors and offspring within the legal framework (M2A) will require all establishments working with donors or with assisted reproduction to report on SAR in donors and offspring. This is already happening today, on a voluntary basis in the majority of EU Member States for donors (baseline - 24 Member States for blood and 17 Member States for tissues and cells), but it will need to be organised in most Member States for offspring (only 2 Member States implementing already). This will generate an extra cost for 2 300 establishments estimated at EUR 5.5 m, and another EUR 0.3 m for their authorities. Furthermore, establishments working with certain categories of donors will have to organise medium/long-term monitoring of safety and health outcomes. Outcome monitoring will also be required for offspring born from donated gametes or embryos. This is estimated to cost EUR 3.6 m per year for about 900 involved establishments , and EUR 0.1 m for their authorities.

The expanded scope towards Substances of Human Origin (excluding organs), might bring future new therapies to be covered. It is however not possible at this moment to specify these, nor the benefit and cost of regulating them under the new framework.

Furthermore, the regulation of bedside processing of BTC, through a light approach that will require a registration and annual activity and vigilance reports – will incur an extra cost of about EUR 6.2 m for around 11 000 hospitals (registered entities ) in the EU. This cost amounts to around EUR 500 per hospital and takes into account a significant saving achieved through the establishment of an EU data platform to support this reporting. This measure will also bring an additional verification cost for authorities (EUR 0.5 m). An investment in the central IT registration tool (EUR 0.2 m) will facilitate registration and reporting for healthcare providers.

Filling the legal gaps and covering unregulated SoHO (such as FMT and breast milk) (M1A) is estimated to require one-off costs for submission and assessment of an authorisation request, and subsequently annual reporting and inspection costs (EUR 1.7 m). These extra costs fall mainly (75%) on a group of about 300 new establishments and partly (25%) on their authorities.

An indirect economic benefit of having up-to-date rules is that these allow for savings on the application of obsolete rules and testing, an undue burden (see section 2.1.6), which is illustrated under section 8.

Member States are expected to report in a common, transparent way on additional (more stringent – option 2 and 3) national requirements (measure M1.3). This is expected to impose only a negligible cost, if this information can be extracted or referenced from the published national rules.

-Option 3 implies higher costs for the EU budget (EUR 1.2 m) as it cannot rely on co-funding with expert bodies. Costs for establishments and authorities are similar to policy option 2.

-In option 2, expert bodies would be co-funded by the EU budget and is expected to cost an additional EUR 0.7 m for the EU, compared to the baseline. However, the extra costs for establishments would then be limited to EUR 3.0 m, while the extra costs for verifying implementation during inspections would be limited to around EUR 0.4, as establishments and authorities can rely on common EU standards.

-In option 1, an extra cost of EUR 6.0 m is expected for the BE/TEs. Large and well-resourced establishments would have the resources, however, for smaller ones this would be a more substantial burden. There are additional costs of inspection of appropriateness and implementation of these standards by NCAs to verify whether these requirements are indeed appropriate for each establishment: this would cost an extra EUR 0.8 m compared to the baseline. EU institutions’ efforts would be limited to general coordination support (EUR 0.1 m).

The creation and maintenance of up-to-date technical rules for safety and quality of recipients (M1B) addresses one of the main undue burdens flagged (section 2.1.6). Costs for this vary across the policy options:

Under this objective, costs for the following key measures are taken into consideration:

Some measures, allowing for more coordination and less duplication, might even entail a saving for those countries that have them already in place (fall under the baseline). Though a conservative decision was taken not to include these savings here, they are however listed as potentials for simplification under section 8.

Finally, the cost calculations took account of differences between Member States. In particular the size of Member States plays a role, with 4 large Member States (DE, FR, IT and ES) accounting for 63% of EU BE/TEs and having already many of the proposed measures in place (see Annex 5). While it was harder to use this experience to quantify benefits, this situation has had a significant influence on the calculation of the baseline, and of the additional costs for the proposed measures/options in such countries, compared to other Member States that have no comparable measures in place to date (see also section 5.1 - baseline).

It needs to be noted that typical BE/TEs are, while of the size of an SME, of a public nature. It has been considered in the drafting and assessment of the proposed options and measures that these establishments have limited (legal) resources to devote to compliance with different national regulations, which complicates the supply of BTC across borders in compliance with regulations of different Member States. Establishing common, EU-wide requirements is therefore considered of benefit for these actors. Only a few for-profit ‘small and medium-sized enterprises’ (SMEs) will be directly impacted by the initiative; these are mostly establishments found in the sub-sector of MAR (private IVF clinics). Therefore, no further SME test was conducted.

One particular challenge was to identify and attribute costs in public settings (public administrations, hospitals) where real hospital costs are often absorbed in overall budgets and unaccounted for. This explains the high variety of costs reported through the study survey, for example for inspections these (time) efforts range from 2 days (direct activities) to 365 days (including daily costs of quality assurance, maintaining records, training, Hazard Analysis and Critical Control Points - HACCP development etc.). Sector experts, both from NCAs and from public establishments, were therefore brought together to identify and agree on reasonable average values and validate key assumptions that have been used to calculate costs (for more details, see Annex 5).

The costs were calculated using the standard cost methodology for all measures (as described in Annex 5), identifying initial one-off (“adjustment”) costs and recurrent administrative costs, and by key stakeholder group. For sake of simplicity, this report presents annual Net Present Value (NPV) costs, based on the net present values of the one-off costs and the administrative costs for a period of up to 10 years. A standard discount rate of 3% is used ,. The details of the calculation, unit costs, and the administrative and one-off costs by each measure and policy option are presented in Annex 5. The detailed breakdown of costs by measure is available in the interactive dashboard . Costs and savings will mainly fall on the BE/TEs (including future ones), other new SoHO entities (e.g., hospitals, to be registered), NCAs (oversight role), and EU institutions.

Impact on patients’ access to BTC processed or used in new ways with proven added value

Safety of BTC processed or used in new ways - evidence on the safety and efficacy is available demonstrating the clinical efficacy outweighs the risk.

Stakeholder confidence on the effectiveness of options in achieving protection of donors and offspring from all avoidable risks

Agility of the regulatory system to respond to avoidable risks - minimum time required for updates in emergency situation (in months)

Ability of the regulatory system to respond to avoidable risks - mobilising relevant scientific and technical knowledge in the BTC sectors

Availability of timely information for risk management on serious adverse reactions and events for patients, donors and offspring

As regards resilience of the sector and mitigating risk of shortages (objective 5), the stakeholders in the sector recognise some benefit of measures for monitoring and notifications, while however also flagging concerns of an increased workload. Monitoring and notification measures for a limited set of critical BTC (M5A) are thus proposed in response to these concerns, to ensure benefits in terms of information for policy makers and transparency, and in case of sudden drops in supply . Option 2 and option 3 in particular are assessed as providing consistent, timely and comprehensive information to Member State authorities. Around 65% of respondents to the public consultation consider that making crisis preparedness plans mandatory (M5B) would bring improvements in the resilience of supply in case of crisis. Providing common guidance on preparedness under option 2 and option 3 in particular are assessed as generating benefits through consistent standardised preparedness plans; with option 1, establishments will have to develop their individual plans.

Case studies have shown that patients access to some BTC has been limited by regulatory classification decisions, even though such therapies could have been provided with sufficient quality, safety protocols and clinical follow up, often at a lower price . The availability of a risk-based pathway could allow for some BTC-preparations that have been regulated as medicinal products in some Member States (e.g. serum eye drops) to be regulated under the requirements of the BTC framework, with an expected impact on their eventual cost and access .

A BTC legal advisory mechanism (M4A) would help clarify EU-level regulatory pathways for BTC innovation across public and private sectors, and publication of its advice is expected to facilitate the development and supply of newly developed BTC, through increasing regulatory clarity. In particular, improved clarity would create an environment in which public sector (and academic) BTC establishments would be more prepared to invest in the development of innovative BTC treatments and organise for more local (diversified) supply - thus further improving patient access to innovation (see also section 6.3.2). While it is important to underline that this initiative will not change the delineation between the BTC and other EU legal frameworks, there is an almost unanimous view that such an EU-level BTC legal advisory mechanism should interact and coordinate with equivalent structures/committees in these other EU (medicinal product and medical device) legal frameworks . Many Member States have such coordination already established at national level , but it is lacking at EU level where it would enable more EU-wide consistency. Note that the ongoing work on the revision of the pharmaceutical framework is exploring a similar, corresponding measure to provide EU-level advice on the applicability of the pharma legislation, in coordination with advisory mechanisms in other legal frameworks (such as medical devices or BTC). Note that this exercise does not look into altering the criteria that define the delineation with other Union legislation, nor into changing the applicable legal framework for certain therapies. Rather, the continuation of the current approach to apply this legal framework unless another Union legal framework applies, allows to ensure that no therapies based on SoHO go without safety and quality requirements. This flexible approach is future-proof towards possible changes in other Union legal acts (e.g., through the pharma revision), where the delineation criteria are set.

Introducing a risk-based authorisation scheme for BTC processed and used in new ways (M4B), with proportionate requirements for evidence of safety, quality and in particular efficacy, is a measure that is strongly supported and all stakeholder groups that expressed an opinion considered that it would significantly facilitate innovation. Not only is this evidence of risk/benefit useful for authorities overseeing safety and quality, but it will also support the assessment of the added value of new BTC therapies by local/national policy makers responsible for healthcare organisation and budgets. The usefulness of using selected evidence from clinical outcome digital registries, as proposed by the GAPP Joint Action , is widely acknowledged . The possibility of publishing a list of authorised processes, as well as of sharing such evidence amongst BTC establishments and Member States’ authorities are strongly supported and expected to further facilitate access to innovation. Providing common guidance to implement such a risk-based authorisation scheme, through expert bodies (option 2) or centrally (option 3), further harmonizes the use of this approach, and hence improves equal access for patients across the EU to safe and effective BTC processed and used in new ways. With option 1, establishments would have to conduct risk assessments and propose clinical studies without such common guidance.

-All measures that harmonise technical standards and increase inter-Member State trust in oversight, will facilitate inter-Member State exchanges of BTC. This is an important factor as transfer of BTC from one region to another can be an essential element of a crisis response, particularly when the crisis is caused by an epidemiological outbreak in one geographical area.

-EU-wide monitoring of critical BTC supplies (including inter-Member State exchanges and imports), for those BTC where a shortage would impact health of citizens, and notification of the authorities in case of significant drops.

-the borderline case studies suggest that having appropriate and proportionate legal requirements for innovative BTC (BTC used or prepared in new ways) reduces costs and, with that, increases the feasibility of reimbursement and access (see Annex 10).

Access to safe and effective innovative treatments (objectives 4 and 5) depends strongly on broader factors that characterise the health systems of the Member States, such as budgets available and ethical decisions, and that are outside the competence of the EU. The measures do not directly impact supply but rather facilitating Member States to identify and manage supply crises. However, a number of measures will contribute to access and continuous supply:

The impact of the proposed measures on the protection of donors and offspring through up-to-date technical provisions (objective 2 – M2A-B) is assessed largely using the same criteria (timely availability of high quality and consistent technical rules, see Table 4), and the options perform in a similar way as for objective 1.

Another key improvement for patient safety can be achieved by filling the existing legal gaps in the BTC framework (M1A). Making 300 FMT and breast milk establishments subject to the BTC framework will allow to address similar concerns on donor safety , and to improve the protection of thousands of recipients of FMT and for pre-term infants receiving breast milk. In the public consultation, 82% of those who expressed an opinion supported the inclusion of these substances in the legislation . Similarly, the obligation for hospitals and healthcare providers to register bedside processing of BTC, where similar levels of safety and quality are expected compared to processing in BE/TE, and consequently report occurrence of adverse reactions, will allow authorities to take appropriate actions to ensure safety and quality for patients in these settings. Over 80% of respondents to the public consultation expressed support to regulate such bedside procedures, though a majority felt they should be subject to less stringent requirements, in particular when these are taking place in operating theatres during surgery .This measure would substantially improve the consistent EU-wide protection of patients ensuring safety, quality and efficacy of such therapies.

§With option 3, a central EU secretariat would need to work with a new committee(s) of experts (similar to those working with expert bodies as under option 2) that would develop the technical standards. A legislative amendment would be needed for each change or update, adding a minimum of 6 months to the procedure, while reducing the scientific independence of the process. Even in an emergency situation the update would go through an approval procedure adding at least 6 months compared to option 2 (see Table 4).

§Under option 2, technical guidelines can be updated by expert bodies and applied by establishments in a short timeframe (1 month in case of an emergency provision; 6-12 months for more substantial revisions), mobilising scientific expertise across the EU.

§In option 1, large, well-resourced establishments will be able to mobilise expertise quickly to revise guidelines, but smaller ones would not have these capacities and lag behind. Larger establishments could therefore respond much quicker than smaller establishments – overall this would result in even more divergence between establishments and between Member States than under the baseline.

Analysis of the social/health criteria shows that the baseline option does not provide for such timely updating of technical provisions. Delays to update rules take at best 1 year, half of that in emergency situations.

When assessing the reduction of avoidable risks for patients (objective 1), the assumption is that if up-to-date technical provisions for ensuring a high level of safety and quality for recipients (M1B) are available in a timely manner, the avoidable risks for patients will be minimised (e.g. no obsolete protocols are used for testing). In addition, if those rules are consistent across Member States, it will allow a similar protection for all citizens, wherever they are treated in the EU. Key criteria used include: time needed for updates (regular and in crisis), available expertise and coherence across Member States.

Efficiency of the oversight - the extent to which the inspections are proportionate to the risks of activities

baseline = Engagement of experts with the relevant expertise and resources for the updates/issuing of technical guidance on safety and quality - inconsistent; across MS and BE/TEs depending on their size and available resources + consistent expertise available to all MS +++ high quality expertise available to all MS

Minimum time required to update/issue technical guidance in an emergency situation on safety and quality by the relevant experts in all MS (months)

Table 3 contains examples of criteria used, their scoring and the corresponding outcome (impact).

In addition to the objective criteria, the preferences and expectations of the stakeholders were also considered. Criteria capturing stakeholders’ opinions are clearly indicated as such in Table 4.1 (Annex 4).

-Where the ultimate impacts could not be quantified (in particular for social and digital impacts), qualitative and quantitative intermediary criteria were used. Such criteria make good proxies for eventual health impacts of the policy options in terms of infections prevented, or quality-adjusted life-years.

-Quantification of the impacts was possible mostly for economic impacts, using the standard cost model.

The impacts of the options were assessed in an iterative process, taking into consideration the assessment of sector experts, through targeted workshops bringing together stakeholders and experts, and including a validation process with the three lead experts of the external study supporting this IA.

Social (health outcomes), economic, digital impacts and impacts on fundamental rights were identified in a first screening and through a mixed method, consisting of literature review, workshops, and surveys. The full list of criteria, methodological notes for scoring and impacts (by criteria and by policy option) can be consulted in Annex 4, Table 4.1interactive dashboard. This table was used as input for the multi-criteria decision analyses (see section 7.1).

Finally, it became clear early in the process that abandoning the current principle on voluntary and unpaid donation (VUD) was not a viable option, from a legal and political perspective, as it would be contrary to with the Article 3 of the EU Charter of Fundamental Rights that prohibits the commercialisation of the human body. Moreover, keeping the differing versions from the blood and the tissue and cell Directives would not help reaching harmonisation in the sector.

Many stakeholders noted a limitation of the measure proposed for objective 5 due to the fact that none of the proposed measures directly intervenes in or seeks to steer supply . However, the proposed measures will allow for Member States to recognise and address supply shortages, and link to further EU initiatives, which may take proactive steps to enhance supply (e.g., Structured Dialogue on supply systems for pharmaceuticals, European R&I Partnership for Pandemic Preparedness ).

On the topic of plasma dependency, there were calls for greater investment in expanding dedicated plasma collection programmes, increasing donor pools as well as other important measures such as training programmes to avoid plasma wastage or unnecessary prescription, or the inclusion of patient blood management measures . While the EU has supported cooperation between Member States and professional associations to address issues such as these in the past (e.g. support to plasma collection , work on Patient Blood management ), regulatory measures in these fields fall outside the scope of EU legal competence (as they relate to national competence to organise healthcare).

Regarding the advisory mechanism on scope of BTC, some actors call on the EU to go further by establishing one common cross-sector EU advisory platform, but this falls outside the scope of the BTC revision. However, the creation of a BTC advisory mechanism will significantly facilitate such a further step, if this measure is adopted through another mechanism.

As noted in paragraph 5.2, there are some domains where the scope for EU action is limited, particularly when ethics or organisational aspects are concerned. For example, some stakeholders called for measures to ensure equal access to MAR technologies . This is not addressed in the policy options as it is Member States that have the legal competence to permit, or not, certain procedures on the basis of ethical considerations.

A SoHO regulatory agency, at EU level, setting safety and quality rules and/or issuing central authorisations for BTC processed or used in new ways (similar to the EMA for medicines). This option is generally considered not realistic, disproportionate and too costly for the size of the sector (as compared to food and pharmaceuticals that each have a dedicated agency).

No change in the legal acts, only encouragement of Member States to work together to agree voluntarily on oversight principles, authorisations of new preparation processes, classification decisions, crisis preparedness. This option would increase divergence between Member States and reduce the possibility of cross-border exchange.

No change to the legal acts; only reactive amendments of the implementing directives to address only the most urgent needs for updating of safety and quality provisions. This option would not fully protect patients against future risks and would not address the drivers of the problems.

A number of further options were discarded early in the process as their impacts were largely undesirable and there was little, if any, support for them among stakeholders.

Regarding the choice of the legal instrument, maintaining Directives was discarded as it had been demonstrated, during the evaluation, to result in high variability in the interpretation and implementation of the rules, causing a lack of clarity and challenges for inter-Member State exchange, which is one of the problems this initiative aims at solving. A Regulation is considered the only suitable format for the new legal act, considering that a key element of the proposal is to establish harmonised measures for Member States and organisations involved in collection, testing, processing, distribution, application of substances of human origin, from donors to patients. Furthermore, a Regulation avoids the burden associated with the transposition of Directives which require Member States to adapt their national law accordingly This sector is mainly public and payment to authorities for inspections and authorisations is not common and consequently resources of NCAs are limited. The possibility for more national stringent requirements, as foreseen in the Article 168(4)(a) of the TFEU, will ensure that the high standards set in an EU Regulation can still be complemented by measures needed to accommodate for national specificities in how healthcare is organised nationally.There are EU legal precedents where Regulations are used even with a legal basis where Member States can implement more stringent measures .

Many of the measures proposed to achieve the objectives will bring simplification through the use of digital tools and platforms linking with each other in a more harmonised way. This initiative will also seek to extend and harmonise their use, allowing key data to be reported only once but used by multiple actors for different purposes. In this way, for instance, BTC donation and use data can be used for sufficiency monitoring, but also for estimating the frequency of adverse outcomes.

These three possible implementations should be considered as 3 sub-options for each of the 3 policy options (as they could be combined with each of the 3 policy options).

·New single system (M6C): create a new unified system – which includes a revamp of the existing elements as well as the addition of the new elements [note that it will be possible to link this data platform to adjacent legal frameworks, where appropriate (such as for clinical trials, communicable diseases, medical devices …)].

·Upgrade and connect (M6B): add missing elements to the existing systems as individual components – plus an additional layer to extract, link and analyse the data.

The technical implementation of the SoHO-X platform can be done via:

The horizontal objective of fostering the use of efficient digital solutions (objective 6) in the new BTC legal framework (SoHO-X platform) builds on the digital measures under each of the previous objectives: development of an IT platform with quality and safety requirements (objectives 1 and 2); supporting oversight (objective 3); for the sharing of authorisation information (objective 4) between Member States, which will facilitate the responsible uptake of and access to new BTC therapies across the European Union; for the exchange of information on supply (objective 5). This data in the BTC sector can become valuable digital assets in the areas of public health and process innovation in the sector. There is a clear potential for improving data flows for reports on BTC-related activities, e.g., on serious adverse reactions and events, on supplies, as well as on the outcomes of BTC .

This option to maintain and harmonise the VUD principle mitigates the risks of financial disincentives and is not only of ethical nature but also strikes a balance between safety and supply. Regarding safety, the risk is that highly remunerated donors can come to rely on the associated income and may hesitate to reveal relevant risk factors during donor screening, to avoid deferral and loss of income. This might also lead to safety risks for the donors themselves related to overly frequent donation. Regarding a sustainable supply, the reliance of the current blood supply on millions of unremunerated blood donors in the EU has demonstrated, not least during the COVID-19 pandemic, that these donors continue donating even in challenging circumstances, when their level of motivation even increases. In contrast, donor payment models typically result in reliance on a small pool of high frequency donors, where a loss of motivation or eligibility to donate can have a damaging impact on supply .

When the BTC legislation was adopted, one objective was to achieve sufficiency through the VUD principle. In this IA, a number of stakeholders, generally representing those working in blood and tissue establishments in the public sector, called for a more stringent enforcement of the principle while others, particularly the commercial plasma collectors, called for a more liberal interpretation and for allowing the coexistence of both donation models (compensated and uncompensated) . The latter group of stakeholders noted that the tissues and cells Directive, unlike the blood Directive, specifically permits compensation of donors for expenses and loss of income and call for this approach to be generalised across all BTC sectors. The only viable option regarding the VUD principle, from a legal and political point of view, is to maintain it (see also section 5.3). Still its definition and implementation will harmonise the differing versions existing today between the Blood and Tissues and Cells Directives, and be adapted the so-called principle of ‘financial neutrality’ recommended by the DH-BIO committee of the Council of Europe on this topic that has received broad consensus. In this way, the VUD principle will be maintained but it will be clarified that Member States may set fixed allowances to compensate donors so that financial disincentives to donation are removed.

For objective 5, the first measure (common to all options, M5A) is to introduce supply monitoring (for all BTC) and notification obligations (for those BTC that are critical for patient treatment ). A second measure (differing according to the options, M5B) is to require crisis preparedness plans to be place . While the EU has no mandate to intervene directly in supply management, reliable monitoring and notification of shortages would help Member States detect sudden drops in supply of BTC, trends towards shortages or dependencies on other Member States or on third countries, and would help them to take appropriate mitigation actions. This monitoring should also address critical devices needed to collect or process BTC and take into account the importance of BTC for the sustainability of the supply of medicines manufactured from BTC .

It needs to be reiterated that no measures are proposed to change definitions or criteria that delineate the border with other legal frameworks. These definitions are set within these other legal frameworks (see section 2.2.3) and any potential revision of those would have to be assessed in the relevant legislative initiative (see section 7.4). Keeping to the current delineation, where this framework applies to all BTC, unless another Union legal framework applies, is a future-proof approach that will allow to accommodate for such possible revisions in these other frameworks. The proposed advisory and consultation mechanism will continue to be useful and effective should the delineation be changed through future initiatives in other frameworks. It also needs to be reminded that, ultimately, classification decisions are made by Member State authorities.

The second measure under objective 4 (common to all options, M4A) is to establish an expert group that can give advice on whether and which BTC requirements are to be applied to ensure safety and quality of a BTC preparation. Such expert group will not make any change to the scope of the EU BTC legislation, and will only provide advice on the applicability of the EU BTC legislation, not on the application of other EU legal frameworks. In the few cases where the provision of advice would relate to regulatory borderlines with other EU legal frameworks, in particular when classification is unclear or when BTC are used as starting materials or in combination with devices or pharmaceuticals (see section 2.1.4), this mechanism will coordinate with equivalent mechanisms in these other legal frameworks to provide for coherent advice. The evaluation had underlined that supporting coherent processes for the classification of BTC processed or used in new ways could simplify the work of authorities . It will therefore also be important to define rules of procedure on e.g., when (triggers, criteria), how (efficient communication channels) and within what timeframes (delays) the expert groups/mechanisms in different EU legal frameworks will coordinate their views. While such rules of procedure cannot be set in a basic act, the tools to do so will be laid down in the basic act.

The clinical trials framework is already used in the EU for newly developed BTC preparations in many Member States . Technical standards for the performance of risk assessments and for the clinical evidence gathering protocols to be followed will be developed either by the establishments (Policy Option 1), provided by expert bodies (Policy Option 2) or defined in EU legislation (Policy Option 3).

For objective 4, to facilitate innovation, two measures were assessed. The first is a risk-based approach to authorise changes in the preparation and use of BTC (M4B, differs according to policy option). Such approach is tailored to the incremental innovation in the public BTC sector ensuring safe access to effective therapies and avoiding under- as well as over-regulation. This measure will extend an existing requirement for tissues and cells to blood and strengthen it in the light of the many new ways that BTC are now processed (some examples are given in point A of Annex 12 where a detailed description of this measure is provided) . An assessment will be performed by the establishment to identify the level of novelty and risk associated with the proposed change. There will be a requirement for clinical evidence to be collected by the establishment, and assessed by the authority, when the degree of risk or novelty warrants this. Clinical evidence requirements could range from intensified monitoring of possible side-effects to clinical follow-up and investigation plans with comparisons to standard therapies, in a manner equivalent to clinical trials in the medicinal product framework at the highest risk level.

For objective 3, all measures are common for the three policy options. Principles to strengthen oversight (M3A) will be established in legislation to provide assurance that NCAs carry out their functions in an independent and transparent manner and with adequate skills and resources. In addition, new and more efficient oversight measures (M3B) to enhance oversight will be introduced, such as joint inspections, risk-based scheduling of inspections, and organisation of EU audits of national oversight systems. The oversight of BE/TEs and other relevant entities will overall follow an approach proportionate to the risks (see annex 16: Details of the measures and policy options) . Measures supporting joint practices, such as joint inspections of establishments (those providing BTC to many Member States, or those having a specific technology/process in place) will bring simplification and efficiency for the NCAs.

For objective 2, principles will be laid down in EU legislation for the protection of BTC donors and MAR offspring and will include mandatory reporting on serious adverse reactions and events (donors can be exposed to health risks for the purposes of donation, for example the egg-cell donors that must be pre-treated with hormones) and allow self-reporting of adverse outcomes by BTC donors (common measures, M2A). Technical rules for donor and offspring protection will be kept up to date (M2B), either by the BTC establishments (Policy Option 1), by expert bodies (Policy Option 2) or by regularly revised legislation (Policy Option 3).

For objective 1, the common measure consists in including in the scope of the framework all SoHO applied to human persons for therapeutic or other purposes (measures M1A), with specific exceptions . There will be no change in the delineation with other EU legal frameworks (it is rather the pharma and medical device frameworks that define the delineation). Thus, this measure will address the gaps in the current legislation for substances of human origin, such as breast milk and FMT , , and the trend towards increased processing of BTC at the patient’s bedside. The technical rules will be kept up to date (M1B); either by the BTC establishments (Policy Option 1), by expert bodies (Policy Option 2) or by regularly revised legislation (Policy Option 3). It needs to be added that the basic act will only organise for how technical rules are set, but not set technical rules itself. These will be set in later implementing acts and/or guidance – according to the Policy Option chosen.

EU development of an interoperable digital platform for publishing relevant information and data exchange; linking existing local, national and EU systems ., with 3 different implementation:

M4B - Risk-based authorisation BTC processed or used in new ways, including clinical data when justified, with guidance [differs by policy option]

Ensure safety and quality for patients treated with BTC therapies and fully protect them from avoidable risks linked to BTC

In addition, a set of common measures to achieve the different objectives are proposed (see below). The table below gives an overview per objective of all measures, specifying those that differ according to the policy option. For the purposes of detailed costing and impact assessment, the measures are further broken down and codified in Annex 16.

Member States may impose more stringent requirements or introduce a temporary derogation if the national, epidemiological situation requires it. In both cases, the EC must be notified.

§sets the technical standards. The legislation will be revised, with the support of a new expert committee, when risks and technologies evolve, to keep the rules up to date;

Member States may impose more stringent requirements or introduce a temporary derogation if the national, epidemiological situation requires it. In both cases, the EC must be notified.

§define technical standards and guidance. Under this option, EU legislation would refer to the latest technical standards of these expert bodies.

§Policy option 2 - joint regulation, builds on the expertise available in established expert bodies, such as the EDQM and the ECDC, which:

§design the risk assessments on novel processes following inter/national or standards from other bodies;

§define their own internal technical standards, and guidance, according to their local needs, evidence review and risk assessments;

The three options differ as regards to the roles and responsibilities of regulators and stakeholders (it should be noted that under each policy option, NCAs inspect the blood and tissue establishments):

Measures are proposed for each of the objectives, with different policy options being explored where technical expertise will be essential for the measures, safety and quality rules or guidance, to be kept up to date. There is a need for those rules that protect patients, donors and offspring (objectives 1 & 2) to be flexible enough to accommodate changes quickly (a new epidemiological threat, a new technology available for testing, new scientific evidence, etc.). Such expertise can also be leveraged to update guidance for the authorisation of innovative BTC (BTC prepared or used in new ways) (objective 4), and for the design of preparedness plans (objective 5). Three policy options have been identified and explored as alternative ways of specifying such more technical rules (see Annex 13 for details on the specific objectives, policy options and measures, and results).

As noted in section 2.1.1, the situation is not the same in all Member States, as some had put in place more stringent measures to protect patients. There are also different practices regarding BTC donors’ protection, with increased follow-up and monitoring on a voluntary basis of donor reactions. This demonstrates that monitoring has been introduced at a national level, either on a voluntary or a mandatory basis, and there is support and willingness of professionals and authorities to monitor and to share the data. There are also different practices in place in Member States as regards preparation process authorisation (as explained in section 2.6), and it was estimated that 19 Member States, covering 82% of all BTC establishments in the EU , already have such practices in place (though with different approaches). A similar proportion of Member States is estimated to already use risk parameters to schedule inspections, combining the current fixed-frequency inspections with more frequent controls for certain establishments. Regarding actions to mitigate risks of shortage, some Member States already have emergency preparedness and contingency plans in place. In a recent survey done by the EDQM on blood emergency/contingency planning , out of the 20 Member States who replied, 16 had plans in place to ensure the continuity of blood supply.

As stated in section 2.3, it is expected that the underlying problems will persist, and even be exacerbated, as the drivers will not disappear (increased demand for many BTC therapies, science and technology bringing new medical and commercial possibilities, and communicable diseases possibly (re)-emerging). It is likely, as mentioned above, that in the face of these trends, and in the absence of EU action, some Member States will take further more stringent measures, to mitigate the absence of updated safety and quality rules at EU level, resulting in an increased divergence in practices followed at national level (see section 2.2.3).

The Commission proposal for a strengthened mandate for ECDC already includes some new or reinforced tasks in the field of SoHO intended to prevent the transmission of communicable diseases via BTC. Those include in particular epidemiological surveillance for SoHO relevant communicable diseases; preparedness and response planning, risk assessments and provision of non-binding recommendations and options for risk management; supported through a dedicated network of experts and authorities in substances of human origin (see Annex 15). Throughout the IA, the assumption will be made that this proposal, which is currently under negotiation, will be adopted without major changes regarding these tasks.

The baseline is a "no policy change" scenario, with the current EU Directives on BTC remaining in force, while some Member States continue to develop and apply more stringent rules as they have done in the past . In the baseline situation, the expert bodies already providing guidance on SoHO, such as the EDQM (Annex 14) and the ECDC (see Annex 15), will also continue working in the field.

Furthermore, throughout the revision process, many parties underlined that the VUD principle remains very important for the BTC framework and should be retained in revised legislation .

It should be noted that objectives 1 and 2 are closely linked, as they both involve setting technical rules for safety and quality to better protect EU citizens. In addition, some measures would be synergetic between both objectives: for example, by including substances not yet in the scope of the BTC legislation, such as breast milk and FMT, this will increase the safety and quality of those substances and therefore better protect patients, but also better protect donors of such substances.

The overall objective of this initiative is to ensure a high level of health protection for EU donors, recipients and offspring and ensure safe and effective access to BTC therapies. As new technologies or risks will continue to emerge, it is desirable that the future BTC framework is more effective, future proof, crisis resistant and agile enough to accommodate new trends and continue providing appropriate safety and quality requirements. As the evaluation identified a number of areas for possible simplification (see paragraph 2.1.6), areas for improving the efficiency of the BTC legislation and simplifying its implementation by all stakeholders will also be explored.

Also, some sector-specific expertise might not be easily available in all Member States. Providing for a common framework that supports joint practices among Member States will promote simplification and efficiency.

Overall, for the five problems highlighted, more collaboration and support among the NCAs would help to address these issues, would bring simplification and would improve the effectiveness of the legislation and the efficiency of its implementation. Sharing information across Member States at NCA level, e.g. on the supply of critical BTC, authorisations of preparation processes, or results of the inspection of an establishment, would help other Member States. Surpluses for a certain BTC should be transparently notified, and authorities could re-use preparation process authorisations already given (by assessing that the procedure is equivalent, without performing again a complete risk assessment or re-assessing the clinical evidence provided) (see Annex 12). The burden associated with this data sharing can be significantly reduced by the provision of an EU digital platform where data can be entered directly by operators and accessed by authorities.

The COVID-19 pandemic highlighted the risks of supply interruptions, the need for adequate donor and recipient protection, and the need for rapid and adequate authorisations of health innovations in the BTC sector (see Annex 9). By providing a framework for cross-border cooperation, based on a common set of rules, and connected to sector-specific expertise, EU-level measures are best placed to address such issues effectively.

The evaluation concluded that “in general, the Directives improved the quality and safety of BTC in a manner that would not have happened, or would have happened more slowly, without EU legislation”. Indeed, significant efforts to raise safety and quality to a common level were made across the EU following the adoption of the legislation. But as technical requirements have failed to keep pace with change over the years, standards have diverged and the evaluation highlighted that “more stringent national requirements, although permitted by the Treaty, limit the EU added value, particularly in terms of exchanges between Member States” .

In addition, there are different practices regarding donor monitoring or reporting of activity and supply data (see section 5.1), and the current situation differs significantly per Member State: four large Member States (DE, FR, IT, ES) already have a lot of oversight measures in place, on the other hand, there are a significant number of smaller, and less well resourced, Member States where the implementation of common EU measures will require more efforts, but will also bring more benefits in terms of strengthening the safety and quality of BTC.

Ever-evolving disease threats, such as Zika and Hepatitis E, which can both