European Union Regulation on Substances of Human Origin (SoHO): What You Need to Know!

Theodorakys Marín Fermín, MD, VENEZUELA Angelo Vasileios Vasiliadis, MD, MSc, PhD, GREECE Tiago Lazzaretti Fernandes, MD, PhD, MSc, Post-Doctorate, Professor, BRAZIL Michail I. Iosifidis, MD, PhD, GREECE Norimasa Nakamura, MD, PhD, JAPAN Fabio Valerio Sciarretta, MD, ITALY

ISAKOS eNewsletters   Current Perspective 2026   rating

Introduction: What Is the SoHO Regulation?

The European Union (EU) Regulation on Substances of Human Origin (SoHO), formally designated as Regulation (EU) 2024/1938, constitutes a substantial revision of the regulatory framework governing human-derived substances, including blood, tissues, and cells, utilized in medical therapies. Of particular relevance to orthopaedic practice, especially regarding orthobiologic interventions such as platelet-rich plasma (PRP), bone marrow aspirate concentrate (BMAC), and stem cell therapies, is the regulation’s adoption of a risk-based authorization model (Figure 1). This model is designed to foster innovation while maintaining stringent safety and quality standards. It allows developers of SoHO-based preparations, including those used in regenerative orthopaedic treatments, to submit clinical evidence commensurate with the intervention’s risk profile and novelty. Consequently, low-risk autologous therapies may receive expedited authorization, whereas higher-risk or innovative applications necessitate comprehensive benefit-risk assessments and ongoing clinical outcome monitoring (Figure 2).

This regulatory approach actively supports the sustained provision and cross-border exchange of orthobiologic therapies, thereby harmonizing requirements across EU Member States. The result is improved patient access to safe and effective treatments for a range of musculoskeletal conditions, including osteoarthritis, tendon injuries, and bone defects. Furthermore, the framework is responsive to technological advancements, incorporating updated technical guidelines developed by authoritative bodies such as the European Centre for Disease Prevention and Control and the European Directorate for the Quality of Medicines & HealthCare.

Figure 1. Overview of orthobiologic therapies, including platelet-rich plasma (PRP), bone marrow aspirate concentrate (BMAC), and stem cell-based interventions.

Figure 2. Risk-based authorization framework for orthobiologic therapies, distinguishing low-risk autologous therapies from higher-risk or innovative applications.

As of August 1, 2026, the SoHO Regulation (EU) 2024/1938 has been in force since July 17, 2024, following its publication in the Official Journal of the European Union. Stakeholders are now entering the final year before full implementation on August 7, 2027, making this a critical period to complete system adaptations, obtain necessary approvals, strengthen documentation and vigilance procedures, and address remaining compliance gaps (Table 1). Certain provisions have already applied since August 2024, while others related to coordination and reporting will not apply until August 7, 2028. Transitional rules remain in place for existing establishments, stored SoHO materials, and selected new activities to prevent disruption. By replacing outdated directives such as the 2004 Human Cells and Tissues Directive, Regulation (EU) 2024/1938 creates a more flexible, digitally focused framework. This new framework harnesses collective expertise and economies of scale within the European Health Union, driving innovation in a sector vital for public health and voluntary donations.

Table 1. What European Orthopaedic Surgeons Should Do Now

Principal Benefits of the SoHO Regulation

• Enhanced safety and quality standards with updated technical guidance: The regulation mandates rigorous, science-driven protocols for donor screening, testing, processing, storage, distribution, and clinical outcome monitoring of all SoHO preparations, including orthobiologics. This ensures the safe, ongoing availability of therapies for conditions such as osteoarthritis and tendon injuries, while facilitating adaptation to new scientific evidence and minimizing risks, all without disrupting established autologous treatments.

• Greater harmonization across EU Member States: By replacing fragmented national implementations of prior directives with a single, directly applicable regulation, Regulation (EU) 2024/1938 establishes uniform standards for authorization, inspection, and vigilance. Orthopaedic clinics benefit from consistent classification and oversight of orthobiologics, such as clarifying borderline cases between SoHO and advanced therapy medicinal products (ATMPs), eliminating discrepancies that previously complicated multicenter studies and pan-European clinical practice.

• Facilitated cross-border exchange and improved patient access: Harmonized standards enable more efficient movement of SoHO preparations between countries. The establishment of a central SoHO Coordination Board and a digital platform further streamlines supply logistics. These measures collectively enhance access to specialized orthobiologic treatments for orthopaedic patients across Member States, reducing waiting times and addressing regional disparities.

• Promotion of safe, effective, and accessible innovation: The regulation’s risk-proportional approach, which imposes lighter requirements for low-risk autologous orthobiologics, coupled with a unified EU data-sharing platform and updated technical guidelines, facilitates the development of next-generation therapies. This environment encourages both research and commercialization of advanced orthobiologic applications, while preserving principles of voluntary, unpaid donation and robust public health oversight.

• Strengthened protection for donors, recipients, and broader populations: Regulation (EU) 2024/1938 extends safeguards to donors, recipients, offspring from medically assisted reproduction, and future generations. It mandates improved traceability, rapid-alert systems, and routine inspections, while incorporating measures to bolster crisis preparedness. For orthopaedic practice, these provisions translate into greater patient assurance regarding orthobiologic safety and more robust supply chains during emergencies.

Controversies Surrounding the SoHO Regulation

Although the SoHO Regulation aims to enhance safety and harmonization, it has generated considerable debate within the orthobiologic community, particularly given anticipated implementation challenges and ethical concerns informed by analogous European regulatory frameworks (Figure 3). Key controversies include:

Figure 3. Overview of the main advantages and disadvantages of orthobiologic treatments under the European Union Regulation on Substances of Human Origin regulatory framework.

• Heightened compliance burdens and increased costs: The regulation expands requirements for entities involved with SoHO preparations, including mandatory registration, authorization, and comprehensive documentation for activities such as processing and distribution. These obligations may impose significant financial and administrative burdens on smaller orthopaedic clinics, innovators, and manufacturers, potentially delaying access to therapies or increasing costs for patients (particularly for autologous treatments such as PRP or BMAC), which may now be subject to stricter oversight.

• Persistent heterogeneity in national implementations: Despite the regulation’s harmonizing intent, divergent interpretations and qualifications of SoHO preparations across EU Member States may persist, resulting in unequal patient access to orthobiologic interventions. For example, certain countries might classify specific stem cell therapies more permissively. In contrast, others apply more stringent standards, thereby perpetuating disparities in orthopaedic care and cross-border exchanges, issues reminiscent of those experienced under previous directives.

• Challenges related to borderline classification: Orthobiologics frequently occupy ambiguous regulatory spaces, straddling categories such as ATMPs, medical devices, or pure SoHO preparations. Although the SoHO Regulation addresses these borderlines through consultations with regulatory bodies such as the European Medicines Agency, complexities in classifying human-derived substances—for instance, distinguishing minimally from more-than-minimally manipulated cells—may lead to inconsistent rulings and complicate the development and approval processes for orthopaedic applications, including tissue-engineered grafts.

• Potential loopholes enabling unproven therapies: Provisions such as hospital exemptions, which permit non-routine use of ATMPs or SoHO preparations under national rules, may create opportunities for clinics to offer orthobiologic treatments lacking robust clinical evidence. This has been a recurring concern in Europe, where such exemptions have facilitated off-label applications in orthopaedics, occasionally exposing patients to risks associated with inadequately characterized products despite requirements for adherence to good clinical practice.

• Ethical concerns regarding marketing and off-label use: The regulation’s emphasis on innovation may inadvertently promote aggressive marketing of orthobiologics with unsubstantiated efficacy claims for orthopaedic conditions, such as stem cell therapies purported to “cure” joint degeneration. This raises ethical issues, including conflicts of interest, misinformation, and exploitation of regulatory gaps, ultimately eroding public trust and underscoring the necessity for rigorous outcome monitoring, concerns echoed in broader critiques of orthobiologic ethics across Europe.

Future Perspectives

In summary, Regulation (EU) 2024/1938 marks a pivotal advancement in the governance of human-derived substances for medical use, with far-reaching implications for orthopaedic surgeons utilizing orthobiologics. The regulation's risk-based and harmonized framework promises enhanced safety, improved patient access, and a robust foundation for innovation. Nevertheless, its implementation is accompanied by notable challenges, including increased administrative burdens, persistent disparities among Member States, and ethical concerns regarding classification and marketing.

The ISAKOS community can play a pivotal role by proactively engaging with evolving regulatory developments, supporting vigilant monitoring, and helping refine oversight processes to ensure the safe, ethical, and evidence-based adoption of orthobiologics in clinical practice. In this regard, future activities of the ISAKOS committee may include: (1) organizing events on the discussion of current and developing orthobiologics laws and regulations with ISAKOS key opinion leaders, and (2) developing guidelines for evidence-based use of orthobiologics considering regional laws and regulations for our membership.

References

1. Amand Eeckhout L. Standards of quality and safety for substances of human origin intended for human application. European Parliamentary Research Service (EPRS) Briefing. European Parliament; September 2024. PE 751.449. Available from: https://www.europarl.europa.eu/RegData/etudes/BRIE/2023/751449/EPRS_BRI(2023)751449_EN.pdf
2. European Commission. New EU rules on substances of human origin. Directorate General for Health and Food Safety; 2024 Jul 17. Available from: https://health.ec.europa.eu/blood-tissues-cells-and-organs/soho-regulation/new-eu-rules-substances-human-origin_en
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Please note: ISAKOS Newsletter Current Perspectives are not peer-reviewed articles. For peer-reviewed articles, please visit the Journal of ISAKOS at jisakos.com.