On 14 July 2022, the European Commission published a proposal for a Regulation on the safety and quality of substances of human origin (SoHO) intended for human application. When adopted, the proposed Regulation will repeal and replace the currently applicable Directive 2002/98/EC on blood (the Blood Directive) and Directive 2004/23/EC on tissues and cells (the Tissue and Cells Directive), with the aim of reforming and modernising the existing EU legislation. The proposal sets out requirements and standards for the safety and quality of blood, tissues, and cells (BTC), as well as other SoHOs, through a single instrument that will apply in all EU Member States in a (hopefully) harmonised manner.
This will be a major development for life sciences companies operating in the EU, including companies developing advanced therapy medicinal products (ATMPs, such as cell and gene therapies) manufactured from or using SoHOs. The Regulation will apply from donation to human application, unless the SoHOs are used in the manufacture of medicinal products or medical devices, in which case the Regulation will apply to donation, collection and testing of the substances only. A public consultation is open until 8 September 2022, and the proposal will also be discussed by the Council and the European Parliament. Once the final text is agreed and adopted, it will come into force, with the proposal setting out a 2-year or 3-year transition period depending on the provision.
The aim of the proposed Regulation is to update and enhance the rules on safety and quality of SoHOs, particularly in light of recent scientific and technical developments in the life sciences sector. Given their age, certain aspects of the current Directives do not reflect technological developments; an evaluation identified the following shortcomings in particular:
- out-of-date technical rules mean that patients are exposed to avoidable risks
- donors of BTC and children born from gamete/embryo donations are exposed to avoidable risks, with limited measures of protection and monitoring currently in place
- cross border exchanges of BTC have been hampered by Member States taking divergent regulatory approaches, which in turn, has reduced trust between Member States
- the full potential of advances in this area are not reaching patients
- patients are vulnerable to interruptions in supplies of BTC in the EU
The COVID-19 pandemic further highlighted certain of these shortcomings, including those relating to supply.
To enable the standards of the draft Regulation to be met and to harmonise the level of protection across the EU for all SoHOs, the proposal seeks to develop and update, with the support of nominated expert bodies, essential technical guidelines to govern SoHO products. This approach will help ensure that standards and guidelines align with the latest scientific and technical expertise, while simplifying cross-border exchange of, and access to, safe SoHO therapies.
The Regulation will allow Member States a degree of flexibility to maintain or introduce more stringent requirements, in particular to ensure alignment with national healthcare systems, though any more stringent measures must be made more visible (including on the internet) to enable easier cross-border exchanges. The proposal sets out that Member States will remain responsible for organisational and ethical decision-making, including around allowing donation of certain SoHOs and access to certain SoHO therapies. While this is similar to the current position under the Directives, where there is divergence across the EU, it is hoped that the new proposal will help to streamline and minimise those differences, and to make them more evident.
Key points in the Proposal
The proposed Regulation is extensive and detailed. We have set out some, but by no means all, key points below:
The current EU framework regulating SoHOs consists of three primary directives: the Blood Directive, the Tissue and Cells Directive, and Directive 2010/45/EU on human organs intended for transplantation (the Organs Directive). The Proposal covers BTCs, repealing the Blood Directive and the Tissue and Cells Directive. Solid organs for transplantation will remain regulated under the Organs Directive.
In addition to BTCs, the proposed Regulation will cover all SoHOs collected from the human body in whatever manner, and will include a broader range of materials that are not covered under the current regime, such as human breast milk and microbiota. The inclusion of a broad definition of SoHOs means that substances that may be applied to patients in the future will also fall within the scope of the Regulation without amendments being required. Further, the scope of defined terms has been updated, with an extension to the scope of some definitions to ensure all uses of SoHOs are covered, such as ‘human application’, and the inclusion of many new definitions, such as ‘release’, ‘import’ and ‘export’, to add clarity and certainty.
The Regulation will set out the SoHO activities that are covered by the Regulation and notably, for therapies developed from SoHOs exclusively for autologous use, only the donor collection requirements shall apply. This will help ensure that the regulation of ATMPs, in particular, is streamlined. The proposed Regulation is not intended to lead to any changes in relation to the delineation of borderline products, with such criteria being already sufficiently outlined in both medical device and pharmaceutical EU law, regulation and European Commission’s guidance.
Protecting Innovation and Improving Safety
The proposal includes an EU-wide procedure for the authorisation of SoHO preparations, thereby simplifying the requirements for companies utilising SoHOs. SoHO preparations are SoHOs that have been subject to certain SoHO activities and meet pre-defined specifications and are intended for a specific clinical indication. The assessment of preparations will be risk based, and include a review of all activities that might influence the safety, quality and efficacy of the preparation, followed by clinical outcome data collection requirements proportionate to the identified risks. A conditional authorisation will be granted where clinical outcome data is required. There may be mutual recognition of an authorisation granted to another SoHO entity, whether in the same or in another Member State, provided that safety, quality and efficacy results can be demonstrated as equivalent. Further, those preparation processes already authorised and lawfully used under the current regimes will still be valid.
The proposal sets out that the current BTC regime contains only limited measures to protect and monitor BTC donors and offspring born through treatment with gametes or embryos. The proposal identifies, in particular, that adverse reaction reporting requirements in relation to donors is too limited, and that testing of gamete donors for genetic conditions are out-dated.
Under the proposed Regulation, SoHOs will be prepared and treated according to specific standards to ensure they are safe for patients, and specific chapters have been included on both ‘SoHO Donor Protection’ and ‘SoHO Recipient and Offspring Protection’. In relation to the latter, which is not explicitly covered under the current regime, emphasis is placed on mitigating the risk of communicable disease and non-communicable disease transmission, including pathogens, toxins and genetic conditions.
Compensation and reimbursement of donors
The current regimes provide for the principle of voluntary unpaid (altruistic) donations of BTC across the EU, though it is the responsibility of each Member State to apply this principle nationally. Although sufficiency of supply through altruistic donations is encouraged under the current regime, this has not proved adequate to protect against the risk of shortages due to supply disruptions.
The proposed Regulation harmonises the differing approaches currently taken under the Blood Directive and the Tissue and Cells Directive, and adapts them to the principle of ‘financial neutrality’ as recommended by the Council of Europe Committee on Bioethics. In this regard, under the proposal, Member States may allow organisations carrying out activities on SoHOs (defined as SoHO Entities) to compensate or reimburse donors for losses incurred on account of their participation in donations through fixed rate allowances, with the setting of an upper limit.
Registration of SoHO Entities
SoHO Entities that carry out activities in relation to SoHOs, including those that import SoHOs, will have to register with their national competent authorities and will need to nominate a responsible person for release of SoHOs for clinical use, and will have obligations in relation to import and export.
SoHO Establishments (a subgroup of SoHO Entities that process and store SoHOs) must obtain a specific authorisation, have a quality management system in place, and designate a physician responsible for specific tasks, including procedures and policies on the criteria for SoHO donor eligibility and the allocation of SoHOs, as well as clinical data collection activities. The proposed Regulation gives discretion to competent authorities as to whether SoHO Entities also require such authorisation where they do not process and store SoHOs, but have significant influence on the safety and quality of SoHOs or carry out activities in connection with multiple SoHO Establishments.
For legal certainty and clarity, a transitional regime for establishments already accredited under the current regime prior to the Regulation coming into force will be introduced, and SoHOs already collected and stored before the date of application of the Regulation may still be used for a certain period of time.
To help avoid supply issues with SoHOs, SoHO Entities will be required to report their annual activity data, and those working with critical SoHOs will need to alert their competent authority in the case of a sudden fall in supply. Entities will also be required to have emergency plans in place to support supply resilience.
Oversight of the sector will be strengthened in a number of respects, although the requirements will be proportionate and risk-based. Competent authorities will be responsible for SoHO supervisory activities. A SoHO Coordination Board will be established and hosted by the European Commission, made up of representatives from the Member States, to promote and support Member States in the coordination and development of the implementing acts. The SoHO Coordination Board will exchange best practices and support joint inspections of SoHO Entities, and may also be asked by competent authorities to clarify their opinion of the regulatory status of borderline products.
The proposed Regulation also provides for the creation of an EU SoHO Platform to support information sharing between competent authorities and with SoHO Entities, facilitating the timely submission of data and reports, the exchange of data, and improving communication and transparency. The platform will allow collection and publication of data on donations, clinical use and possible adverse reactions, under clear governance and in line with data protection. The European Commission will utilise this Platform to review the monitoring indicators periodically, and the Platform will provide a central hub for access to information on registrations, authorisations and technical guidelines.
The European Commission will evaluate the impact of the Regulation after five years, collecting additional data, including on the costs, usability and integration of the new approach.