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Aerial View of Waves

LDT Regulation in US and EU: Similarities and Differences

Laboratory Developed Tests (LDTs) play a key role in global healthcare, allowing health institutions to develop specific diagnostic tools that are not mass-produced or commercially available. During the COVID-19 pandemic, they received spotlight attention with an unprecedented demand for decentralized, rapid diagnostic tools. They play a vital role in many emerging trends, such as personalized medicine, gene expression profiling, and pharmacogenomics.

The United States (US) and European Union (EU) are currently in different stages of regulation that aims to balance patient care, innovation, reliability, and safety. The scope of regulated products is, however, similar. The FDA defines the term Laboratory Developed Test (LDT) as “an IVD that is intended for clinical use and designed, manufactured, and used within a single laboratory”.[1] The Regulation (EU) 2017/746 of the European Parliament and of the Council of 5 April 2017 on In Vitro Diagnostic medical devices (IVDR) in the European Union refer to diagnostic reagents manufactured as In-House Devices (IHDs), which are used only within EU health institutions.[2]

While US and EU regulatory frameworks share common objectives, it is also important to understand where policies diverge. Given the size and influence of the US and European markets, understanding key similarities and differences helps inform your global regulatory strategy.

Similarities in Regulation between US and EU:

  • Both consider the tests a category of In Vitro Diagnostics (IVDs).  On April 29, 2024, the FDA finalized a rule that explicitly classifies LDTs as medical devices, regardless of whether they are developed by clinical laboratories or conventional IVD manufacturers. This ends a long era of enforcement discretion when US labs did not face the same level of approvals and oversight as commercial device makers.  It also brings US policy closer to the EU approach. The IVDR in Europe provides an over-arching regulatory framework that includes tests made and used by healthcare institutions as well as conventional device manufacturers.

  • Both utilize a risk-based approach. LDTs are categorized based on complexity and potential risk to patients, with requirements increasing in proportion to patient safety risk. The FDA ruling sets a timeline for high-risk and medium-risk lab tests to meet pre-market review requirements within the next four years. FDA Commissioner Robert Califf cited risk as a primary justification for the new ruling, stating “the risks associated with most modern LDTs are much greater than the LDTs used when FDA’s enforcement discretion approach was adopted many years ago.” Likewise, IVDR requires risk management to be applied to IHD, and demands a Quality Management System (QMS) that is appropriate for the degree of manufacturing complexity of the IHD.

  • Both emphasize laboratory standards. The FDA and IVDR will both require strict standards like ISO Standard 15189 for competence and quality of laboratory systems, processes, reporting, equipment, and personnel for medical laboratories.

  • Both emphasize increased regulatory oversight. The FDA ruling could impact tests run by over 12,000 separate US laboratories. The increased scope of compliance will be a significant change for hospitals and clinical laboratories, who previously raised concerns with the FDA plans.  The EU legislation to treat lab based IHD also starts to go into effect in May 2024. This could impact approximately 41,000 European laboratories, based on a 2021 report by the European Society for Laboratory Medicine (ESLM).

 

 

 

Differences in Regulation between US and EU:

  • Definition by Central Authority versus Collaborative Framework.  The US has a specific and centralized definition of LDTs, encompassing tests developed, manufactured, and used within a single lab. For IVDR, the term IHDs has been coined by the Medical Device Coordination Group (MDCG), an entity with representation from all EC Member States, to cover the IVDR definition of – and requirements for – devices manufactured and used only within a health institution established in the EU.

  • Exemptions. The FDA’s new LDT ruling exempts certain types of tests, including forensic tests used for law enforcement, Human Leukocyte Antigen (HLA) tests for high complexity histocompatibility testing, public health surveillance tests, and low-risk tests for rare diseases.

  • Transition period: The FDA ruling prescribed the following 5 stage phase in period for ending its enforcement discretion of LDTs:

    • Year 1 - Medical Device Reporting, Corrections and Removals,

    • Year 2 – Establishment Registration, Device Listing, and Investigational Device Exemption (IDE), and

    • Year 3 - Quality Management Systems (QMS),

    • Year 3.5 - Pre-Market Review for Class III-LDTs,

    • Year 4 – Pre-Market Review for Class II and certain Class I LDTs.   

 

 

The IVDR defines a clear process where all IHDs are partially exempted from regulatory requirements; however, IHD are only allowed to make use of this exemption if they meet all requirements set out in IVDR Article 5(5). Under this scheme, IHD must comply with the IVDR General Safety and Performance Requirements (GSPR), ISO Standard 15189, and be manufactured under an appropriate Quality Management System (QMS). Furthermore, the specific need for using the IHD must be justified, and documentation and traceability requirements must be fulfilled. The EU timeline entails the following key dates:

  • Compliance to the GSPR and Article 5(5)(a) apply to all IHD since May 26, 2022.

  • All other Article 5(5) clauses become applicable as of May 26, 2024 except the justification that the target patient group´s specific needs cannot be met or cannot be met at the appropriate level of performance in another way than by manufacturing and using the IHD (Article 5(5)(d))

  • Tests within this exception group have a deadline of May 26, 2028, with a proposal currently on the table to further extend this deadline to May 26, 2030.[3]

  • Post-market surveillance. In the US, FDA ruling applies a risk-based approach for post-market surveillance and medical device reporting. Health institutions in the EU are required to review experience gained from the use of their IHDs and take all necessary required actions. The National Competent Authority can inspect health institutions that make and use IHD.

  • Transparency.  The IVDR emphasizes transparency and requires health institutions that use IHDs to publicly identify themselves as well as the IHDs involved. FDA requires broader enforcement oversight and registration of establishments, listing of devices, and post-market surveillance but does not specifically mention new requirements to self-identify in the same manner as required for IVDR. 

  • Possible Future Legislation in the US. The VALID (Verifying Accurate Leading-edge IVCT Development) Act was a measure to regulate LDTs through Federal legislation. It was proposed in the US Congress in 2021 but failed to gain final approval. Jeff Shuren, director of the FDA’s Center for Devices and Radiological Health (CDRH), acknowledged that any future actions in Congress could supersede the FDA ruling.

 

Despite significant efforts to harmonize international regulatory requirements, there is still no universal or consistent approach to compliance in the US and EU. However, the FDA and IVDR are demanding more oversight on increasingly complex LDTs and IHD to ensure patient safety. Developing a global regulatory compliance strategy helps innovators ensure readiness of their Quality Systems, design analytical and clinical studies, and prepare required technical documentation for significantly changing US and EU regulatory landscapes. Innovators that proactively prepare for regulatory changes will be positioned to capitalize on new opportunities for developing novel LDT/IHD diagnostic tests for rapidly expanding fields of genomics, predictive screening, point-of-care diagnostics, and precision medicine.

This article was co-authored by The Landrich Group and Qarad/QbD IVD. The Landrich Group (www.landrichgroup.com) is a US-based Clinical Research, Quality and Regulatory Consulting Firm based in Alameda, California. Qarad/QbD IVD (www.qarad.com) is a Belgium-based company offering Expert Consultancy in EU regulations for In Vitro Diagnostics. Landrich and Qarad are committed to supporting your global regulatory strategy for In Vitro Diagnostics.

For more information about our services, please contact us at admin@landrichgroup.com for a complimentary consultation.

Additional Reference Sources:

US

  1. FDA LDT Ruling. https://www.fda.gov/news-events/press-announcements/fda-takes-action-aimed-helping-ensure-safety-and-effectiveness-laboratory-developed-tests

  2. FDA Draft Guidance: Framework for Regulatory Oversight of Laboratory Developed Tests (LDTs) – October 2014

  3. FDA Discussion Paper on Lab Developed Tests (LDTs), January 13, 2017

  4. FDA Laboratory Developed Tests: https://www.fda.gov/medical-devices/in-vitro-diagnostics/laboratory-developed-tests

  5. US Food and Drug Administration (FDA): https://www.fda.gov/medical-devices/in-vitro-diagnostics/direct-consumer-tests

  6. Centers for Medicare & Medicaid Services (CMS): https://www.cms.gov/medicare/quality/clinical-laboratory-improvement-amendments/guidelines-laboratories

  7. FDA: https://www.fda.gov/medical-devices/in-vitro-diagnostics/direct-consumer-tests

  8. VALID Act: https://www.fda.gov/drugs/guidance-compliance-regulatory-information/laws-acts-and-rules

 

EU

  1. European Commission - IVDR Information: https://euivdr.com/

  2. MDCG 2023-01 Guidance on Health Exemption under Article 5(5) of EU Regulation 2017/245 and 2017/746.  https://health.ec.europa.eu/system/files/2023-01/mdcg_2023-1_en.pdf

  3. EU LDT Expert Group: https://pathology.nl/wp-content/uploads/2021/07/Guidance_use_LDT_IVDR_taskforce_vs2.0-final-10122020.pdf

  4. https://health.ec.europa.eu/medical-devices-sector/new-regulations_en

  5. European Commission: https://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:32017R0746

Additional Sources

  1. https://www.cancer.org/content/dam/CRC/PDF/Public/8493.00.pdf

  2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8294224/

  3. International Organization for Standardization (ISO): https://www.iso.org/standard/56115.html

[1] https://www.fda.gov/medical-devices/in-vitro-diagnostics/laboratory-developed-tests#:~:text=Laboratory%20developed%20tests%2C%20or%20LDTs,which%20meets%20certain%20laboratory%20requirements.

[2] The IVDR applies to the EU and additional countries within the European Economic Area such as Norway and Iceland.

[3] https://health.ec.europa.eu/system/files/2024-01/mdr_in-vitro-proposal.PDF

Screenshot 2024-04-18 at 10.13.50 AM.png
FDA Proposed Timeline for LDT Regulation

EU Timeline for In House Device Regulation

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