A detailed examination of Laboratory-Developed Tests (LDTs) and In-House Devices

The Power of Precision Medicine

Laboratory-developed tests (LDTs), generally known as in-house devices, play a crucial role in diagnostic laboratories worldwide. Although both in-house devices and LDTs are created and utilized within a healthcare facility, the term “LDT” is generally used in a more specific context to refer to tests made in labs for clinical or research purposes. On the other hand, “in-house devices” may encompass a broader range of medical devices beyond diagnostic tests, though LDTs are a significant subset of in-house devices (Ref 1).

These customized tests are designed, developed, and validated within a clinical or research laboratory setting. They cater to specific diagnostic needs that may not be met by commercially available assays. This article will explore the definition and requirements according to the In Vitro Diagnostic Regulation (IVDR) in the European Union and the Food and Drug Administration (FDA) in the United States.

LDTs and In-House Devices Demystified

In-house device: In the EU, a device that is manufactured and used only within a health institution/legal entity* established in the Union and that meets all conditions set in Article 5(5) of the MDR or IVDR.

Lab-developed tests are diagnostic assays created by individual laboratories to detect specific genetic mutations, pathogens, or biomarkers. These tests are not sold or distributed commercially, but should be used within the same health institute or organization. LDTs are especially valuable for diagnosing rare diseases and cancer, investigating emerging infectious agents, and addressing unmet clinical needs.

The Regulatory Landscape of LDTs and In-House Devices: EU vs. US

EU Regulations perspective

The European Union’s In Vitro Diagnostic Regulation (IVDR) (Ref 3) governs in vitro diagnostic medical devices. In-house devices, such as LDTs, are not subject to MDR and IVDR regulations, provided that the healthcare institution complies with the stipulations set forth in Article 5(5) of the applicable Regulation (Ref 1).

Nonetheless, the IVDR recognizes the hazards posed by LDTs and restricts the capacity to create products internally by stipulating requirements that labs solely engaged in the development and usage of in-house tests must meet. These include the manufacture and use of the products shall take place within the framework of suitable quality management systems (QMS), the healthcare institution’s laboratory shall be accredited with the EN ISO 15189 standard, and where appropriate, with national regulations including national accreditation rules (Ref 3). However, as the manufacturing process of a device and the compliance to the relevant requirements of Annex I is not in the scope of EN ISO 15189 alone it does not constitute an appropriate QMS for the manufacture of in-house IVDs. Article 10(8) of the IVDR describes the minimal aspects that a QMS for manufacturing CE-marked medical devices should cover.

The healthcare organization shall provide justification that the specific needs of the patient target group cannot be met at the indicated level of performance by a similar product on the market. The IVDR specifies requirements for laboratories that create and employ in-house tests in Article 5(5). Additionally, the product must adhere to the fundamental safety and performance standards set out in Annex I (GSPR).

Other conditions where Article 5(5) applies (Ref 1):

• If a healthcare institution alters the intended purpose of a CE-marked equipment for use within the institution.
• If a healthcare institution assigns a Research Use Only (RUO) product a purpose that aligns with device regulations when used within the institution.

Note that In‐house devices may include RUO products as components, provided that the resulting in‐house device complies with the requirements of Article 5(5). For example, a PCR master mix manufactured in a health institute to run PCRs on human DNA/RNA specimens.

FDA perspective

In the United States, the regulation of LDTs has been historically managed under the FDA’s enforcement discretion, which meant that they were not subject to the same pre-market approval requirements as commercial tests. However, this landscape has evolved, and the FDA has taken steps to regulate LDTs more closely. In 2021, FDA issued a draft guidance outlining its intent to regulate LDTs. Some potential requirements for LDTs under the FDA’s oversight may include:

1. Pre-market Review: LDTs may need FDA pre-market review for safety and effectiveness.
2. Quality Systems: Laboratories developing LDTs may need to establish and maintain quality systems to ensure accurate and reliable test results.
3. Reporting and Compliance: Adverse events must be reported, and post-market surveillance followed.

See references 5, 8, and 9 for more detailed information.

The Creation of In-House Devices In Sweden

The national competent authority for medical device regulation is the Swedish Medical Products Agency (MPA) or “Läkemedelsverket”. It is mentioned on their website that after May 26, 2022, HSLF-FS 2021:32 (Ref 7), along with supplements to MDR and IVDR, will also apply to in-house manufacturing of IVD products. The following applies to in-house devices in the future, according to LMV (Ref 6):

• From May 26, 2024, the IVDR takes over the requirements for QMS, documentation, declaration of conformity, follow-up, and evaluation for in-house manufacturing (Article 5.5 b, e, f, g, h, i). Requirements for the healthcare institution’s laboratory to adhere to the standard EN ISO 15189 or, as applicable, national provisions related to accreditation are applicable (Article 5.5 c).
• From May 26, 2028 justification required that the in-house manufactured product serves a need that cannot be met by any equivalent product available on the market (Article 5.5 d).

Läkemedelsverket also requires healthcare providers that manufacture in-house in vitro diagnostic medical devices (LDTs), to register or report their device to IVO, “Institution för Vård och Omsorg”.

The Future of Diagnostics with LDTs and In-House Devices

In the realm of personalized and innovative medical lab testing, LDTs hold a significant position. However, the introduction of the IVDR and the lack of clear interpretation in the EU regarding LDT definition, standards application, and documentation extent are causing uncertainties for labs and regulatory bodies. The article published on SpringerLink in 2021 (Ref 2) highlights these challenges and emphasizes the need for common criteria to ensure LDTs’ quality, safety, and performance. These criteria could serve as key elements in future international consensus guidance. As we navigate through this evolving landscape, the impact of potential regulatory changes will be crucial in shaping the future of LDTs in precision medicine.

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Our experts at GBA Key2Compliance have extensive experience in medical device regulations and assisting legal entities in developing their LDT or in-house devices. Keep an eye out for further updates by visiting our web site, and connecting with us on LinkedIn!

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*The national competent authority may clarify how the legal entity is understood nationally. For example, when there is just one healthcare organization (one organizer) within a hospital, that hospital might be considered as a single legal entity.