First published in our Biotech Review of the year – issue 9.
Although a draft legislative proposal is yet to be published, several EC publications from 2021 indicate the areas which will likely be subject to changes. In this article, we take a look at some of these areas and comment on the impact these revisions might have on patients and BTC-based treatments in the EEA and Northern Ireland.
Legislative landscape and the ATMP Regulation
For over 15 years, the quality and safety of human BTC collected in or imported into the EEA have been regulated by two EU directives (the BTC Directives). The legislative reform of the BTC Directives was triggered by an EC evaluation published in October 2019, which highlighted several gaps and shortcomings in the framework. It is these gaps that the EC aims to address, but the proposals are likely to have an impact on the wider regulatory landscape in this area, as the BTC Directives are only a part of the tapestry of legislation relevant to BTC in the EEA and Northern Ireland.
The BTC Directives set standards for the quality and safety of BTC, from collection to clinical application, including testing, processing, storage and distribution. Most commonly, BTC are infused or grafted directly into a patient in the course of a blood transfusion or tissue transplant. However, BTC may also be used in the manufacture of advanced therapy medicinal products (ATMPs), cell and gene therapy medicinal products with ground-breaking therapeutic potential. The approval and marketing of ATMPs in the EEA is regulated by the EU ATMP Regulation , which classifies them, brings them within the overall EU medicines regime and sets specific preconditions to authorisation, including requirements that the starting materials are compatible with applicable BTC Directives and that any medical device characteristics of an ATMP are regulated in accordance with EU medical device regulations.
The EC has published a roadmap describing the scope of the initiative to update the BTC Directives and outlining potential policy options. In the first half of 2021, the EC organised online stakeholder consultations and workshops to gather views on the proposed policy options. Workshop summary notes provide insight into the aspects of the BTC Directives that the EC aims to revise, but also indicate the proposed policies which concerned stakeholders. The consultation has not been entirely straightforward: we understand that there has been some disquiet in the wider industry regarding the representation of attendees at some of these workshops.
1. Strengthen oversight
An overarching theme driving the EC’s proposed revisions is strengthening the oversight of the BTC sector to ensure that rules are implemented uniformly throughout the EU, primarily to improve inter-Member State confidence and better facilitate the cross-border exchange of BTC.
The EC’s roadmap set out three potential policy options for the new oversight approach. Throughout the various workshops, attendees voiced their support for the second of these options. This involves a system of co-regulation, with the EU-level regulations on safety and quality being supplemented by technical rules and specifications set by EU bodies which would apply to national establishments involved in BTC. This policy option also includes risk-based inspections by national authorities, EU-level audits of national control mechanisms and joint compliance inspections by two or more Member States.
2. Borderline with other regulatory frameworks
The summary notes indicate that the EC identified that the borderlines between BTC legislation and the frameworks governing medicinal products, such as ATMPs and medical devices, are not sufficiently clear and that uncertainty as to which regimes apply is a barrier to innovation. The discussions regarding changes in this area have provoked much debate.
There are significant differences between the various treatments derived from BTC. One aspect is the processing technique applied to the collected BTC. At the simple end of the scale, the BTC can be administered to a patient in the same form as it was collected, with almost no processing activity taking place (e.g. blood transfusion). At the other end of the scale, the collected BTC can be significantly manipulated and processed to transform it from a raw substance of human origin into a sophisticated medicinal product such as skin or a suspension of cardiomyocytes. At some point on this scale, the BTC ceases to be considered as solely BTC and becomes classified as an ATMP. But it’s not just about the degree of processing: another aspect that can vary is the intended use. If a treatment involves the BTC being used for a different essential function in the recipient than it was in the donor, then even with the most minimal processing, the product will be classified as an ATMP under the ATMP Regulation.
It appears that the consultation participants and workshop attendees support the establishment of a multi-disciplinary BTC advisory mechanism to promote a consistent approach to borderline products between BTC authorities. In addition, there is a suggestion that a cross-sectoral EU-level mechanism could be established to facilitate discussions between authorities in the BTC and pharmaceutical fields and provide clarity as to which regulations apply to novel substances. This appears to be a sensible proposal and in line with the theme of harmonisation. Currently, there is variation in how Member States implement the different frameworks governed by the BTC Directives. We have seen the EC take steps to harmonise medical devices legislation by replacing the old directives with new regulations which apply directly throughout the EU, eliminating the possibility of variable national implementation.
However, in our view, the wording of the published documentation is confusing, and it is not clear why the EC has sought to address any perceived lack of clarity regarding the classification of novel therapies in the revisions to the BTC legislation as, regardless of whether a therapy is classified as an ATMP or not, if it involves BTC it must comply with the requirements under the BTC Directives. In addition, whether or not a product is regulated as an ATMP depends on the interpretation of the definitions set out in the ATMP Regulation alone.
3. Regulating point-of-care BTC processes
Two important applications of BTC are in transfusions and transplantations. Most transfusions and tissue transplants involve BTC being taken from a donor and applied to a different individual. By contrast, autologous transfusion or transplantation involves the patient’s own BTC being returned to them after processing. This processing sometimes takes place at the bedside or during surgery with re-administration at the same location. Because the BTC Directives do not apply in these circumstances, the processing and testing of BTC is left unregulated. There was general support among stakeholders for proposals aiming to bring these procedures within the BTC regulatory framework to ensure safety and efficacy across the EU. However, in our view, it could be questionable whether regulating medical practice in this way falls within the legal competence of the EU.
Since many of these methods of processing BTC involve medical equipment and are carried out in hospitals, it has been suggested that they could be regulated under the medical device framework or national hospitals’ oversight. However, workshop attendees favoured regulation at an EU level under the BTC legislation, and the EC proposes to introduce an authorisation procedure for preparation processes involving BTC. The authorisation procedure for each process would be proportionate to the risks involved, would focus on efficacy and could involve mandatory registration as well as data and vigilance reporting obligations. Some of these processes transform BTC to such an extent that the product administered to the patient is classified as an ATMP.
4. Donor protection
In general, a significant overhaul of the provisions relating to the protection of BTC donors is expected, as at present the protection afforded by the BTC Directives is considered to be limited. The reporting of donor reactions is currently mandatory only when the safety or quality of the donated substance itself has been compromised. The consultation documentation indicates strong industry support for mandatory monitoring and reporting of donor reactions regardless of the quality of the donated substance. In addition, there is strong industry support for the new measures to strengthen the protection of donors to be codified in the EU legislation and for a system of co-regulation, with greater involvement of EU bodies.
There have been specific discussions regarding proposals to increase the protection of egg donors and children born from medically assisted reproduction (MAR). There are suggestions that an EU-level gamete donor registry could be established as a measure to protect egg donors and children born from donated gametes and embryos. At present, there is no system in place to monitor the health of such children, and it appears some measures may be introduced in this area. However, this is a sensitive subject as any new measures must not create or amplify misleading associations between children born from MAR and certain genetic health conditions (and must also not fall foul of any data protection related laws). In addition, new measures must not reduce the donor pool any more than what is necessary to protect the children born from the donated gametes and embryos.
5. Definitions and scope of BTC legislation
The EC proposes to harmonise and update some key definitions in the BTC Directives. New developments in this field since the adoption of the legislation have rendered many definitions unclear or outdated. There are also inconsistencies between the definitions contained in each of the two BTC Directives and further inconsistencies between how Member States have implemented the BTC Directives.
In updating some of these definitions, the EC seeks to expand the scope of BTC legislation to include additional substances of human origin not currently covered and substances for different intended purposes. Faecal microbiota, human milk, serum eye drops and platelet-rich plasma were named in the consultation document as substances that would be brought within the scope of the BTC legislation.
It will be interesting to see how borderline substances are addressed in the revisions as there is often ambiguity over which framework applies to novel treatments, and some definitions may be tweaked to deliver greater clarity in this respect.
6. Ethical principles
There are ethical issues intrinsically linked to BTC applications since all BTC material originates from donations from individuals. These issues include voluntary unpaid donation, the prohibition on profiting from the human body, and the appropriate uses of BTC. Ethical issues are generally delegated to Member States to consider, but some impact the safety and quality of the supply and also engage wider EU fundamental rights. The EC proposes to revise how some ethical issues are addressed in the BTC framework. The proposals suggest that this could involve introducing provisions related to consent and ensuring that donors are made aware of the potential uses of their donated material.
7. Technical rules and authorising novel BTC
The EC indicates that current requirements under the BTC Directives for authorising new processes involving BTC and new clinical uses of BTC are not up to scratch. The documentation states that the current requirements lack clear rules for demonstrating the efficacy of these new processes and clinical uses and as a result, there is a lack of standardisation and mutual recognition across Member States. Proposals in this area involve referring to BTC monographs to determine whether a clinical application is novel and amending the legislation to explicitly set out the requirements and procedure for authorising novel BTC processes.
In addition, it is likely that there will be updates to the technical rules set out in the BTC Directives, which have not kept pace with innovation. The summary notes reveal support from workshop attendees for this, with a preference for how technical rules are updated depending on the type of rule. For example, there is industry support for some technical rules to be defined and updated by professionals, some by expert bodies and some by the inclusion of detailed provisions in the BTC legislation itself.
8. Sufficiency of supply
There is widespread industry support for introducing measures to achieve self-sufficiency of plasma-derived medicinal products, as currently two-thirds of the plasma used to manufacture BTC products is imported from the US. In addition, there is industry support for reporting obligations to be introduced to enable regular supply monitoring of tissues and cells at the national and EU level, and the introduction of emergency contingency measures for when their supply is threatened.
At the time of writing, the EC plans to present revisions to the BTC Directives in the first quarter of 2022 and it will be interesting to see how many of the proposals set out above are taken on board. Watch this space.
 Directive 2002/98/EC and Directive 2004/23/EC.
 Regulation 1394/ 2007
 Under Directive 2001/83/EC and Regulation 726/2004.
 Regulation 1394/2007 and Part IV, Annex I, Directive 2001/83.
 Recital 14 & Article 3, Regulation 726/2004; paras 3.1 & 18.104.22.168. Part IV, Annex I, Directive 2001/83.
 Article 2 Regulation 1394/2007; Para 2.2(a), Part IV, Annex I Directive 2001/83.
 Including storage
 We note that the BTC Directives relate solely to the safety and quality of the BTC and not efficacy. The efficacy of BTC products falls within the remit of other European legislation.