The EU Regulates Medical Laboratories – Are Laboratory Developed Tests Still Allowed?

1. Why you might have to reduce the range of tests you offer

The EU legislator is regulating laboratory developed tests for the first time with EU Regulation 2017/746 on In Vitro Diagnostic Medical Devices(IVDR). As a result, its requirements apply directly to laboratories that offer tests they developed themselves.

Most of these requirements are not new, but the additional requirements mean that you, as a medical laboratory, are no longer allowed to offer certain LDTs. For example, this can be the case if a manufacturer offers a comparable CE-IVD device on the EU market.

What this means for you and how to avoid this problem will be explained later in this article. But first let us address the basics.

2. In-house IVD: What are they?

a) Definition of terms

The IVDR does not define in-house IVD or LDT under the definitions in Article 2 but provides the following description in Article 5:

The guidance document MDCG 2023-1 of the Medical Device Coordination Group designates corresponding tests as "in-house devices":

The US FDA defines the term "Laboratory Developed Tests" as follows:

b) Differentiation from medical devices manufactured in-house

LDTs, or ‘in vitro diagnostic medical devices from in-house production’, must themselves be differentiated from ‘medical devices from in-house production’. In the case of a ‘medical device from in-house production’, we would talk about in-house production according to Article 5(5) MDR.

c)Where in-house IVD are used

Medical laboratories examine specimens derived from the human body: Tissue and body fluids (e.g., blood, urine, cerebrospinal fluid, etc.). To make diagnoses or to obtain information relevant for the diagnosis, laboratories use:

1. Commercial in vitro diagnostic (IVD) medical devices, or
2. non-CE-marked, modified, or self-developed tests, known as LDTs

Anywhere CE-IVD devices are used, LDTs can be used as an alternative. However, the IVDR limits the use of in-house IVDs to what it calls health institutions and defines such institutions as follows:

For this reason, a medical laboratory creates an LDT when it:

• uses products or procedures it has developed itself,
• uses non-IVD devices in diagnostic procedures (e.g. for research use only, RUO),
• combines products or processes that are not intended for the combination, or
• uses a CE-IVD device outside its intended purpose, e.g., when they:
  • misuse the device (off-label use) or
  • modify commercial devices (including if they deviate from the instructions for use of conventional IVD devices).

If one or more of these criteria apply to your tests, the requirements in the next section apply in full to your medical laboratory.

3. Legal requirements

a) Previous requirements for in-house IVD in Germany

Putting in-house IVD into service was only permitted according to section 12 of the MPG if the essential requirements of EU Directive 98/79/EC on In Vitro Diagnostic Medical Devices (IVDD) have been met. This means that if you have already offered an LDT before May 26, 2022, you must comply with Annex I of the IVDD.

Medical laboratories also have to comply with the “Richtlinie der Bundesärztekammer zur Qualitätssicherung laboratoriumsmedizinischer Untersuchungen” the Rili-BÄK for short. This is established in the Medizinprodukte-Betreiberverordnung (MPBetreibV). This has not changed since the IVDR came into force.

b) Requirements of the IVDR for in-house IVDs:

The IVDR wants to continue to permit in-house devices without the involvement of notified bodies and without CE marking (clauses 28 and 29 in the foreword section). As a result, in Article 5(5), the IVDR sets out the requirements that laboratories must meet for tests manufactured and used only within health institutions (this also includes the remote use of in-house IVD software; see MDCG 2023-1 3.2.2). These include:

1. For all in-house IVDs, conformity with the essential safety and performance requirements according to Annex I of the IVDR must be demonstrated.
2. The manufacture and use of the devices occurs under appropriate quality management systems.
   • Neither Rili-BÄK nor ISO 15189 establish requirements for the development and manufacture of IVD devices. They also only provide incomplete specifications for the validation of these devices. As a result, it can be concluded that the requirements of section 7 of ISO 13485 apply.
3. The health institution justifies in its documentation that the target patient group's specific needs cannot be met, or cannot be met at the appropriate level of performance by an equivalent device available on the market.
   • This is possibly the most significant new requirement because LDTs for which there is an equivalent CE-IVD device on the market no longer have a right to exist.

Further requirements from Article 5 (5), such as

• a publicly available declaration,
• the surveillance of the devices,
• the prohibition of distribution and
• the prohibition of industrial-scale production

were already required by the MPG and the associated ordinances.

The Johner Institut supports medical laboratories in the implementation of all IVDR requirements. Contact us if you have any questions.

c) FDA requirements for laboratory developed tests

At this point, it is worth taking a look across the pond because the FDA has been considering the regulation of LDTs since at least 2010, but has not yet been able to fully enforce anything. It is aware of the risks posed by incorrect or inappropriate treatment of patients that can result from the use of insufficiently controlled “high-risk LDTs”. The FDA no longer considers the previous “enforcement discretion” to be adequate for all LDTs.

Therefore, in 2014 the FDA published a draft “FDA Notification and Medical Device Reporting for Laboratory Developed Tests (LDT)” and collected feedback. This flowed into a “Discussion Paper” which the FDA published in January 2017.

In this document, the FDA wrote that it considers it problematic that a test developed by an IVD manufacturer is regulated differently to an identical test developed by a laboratory. This would undermine its risk-based approach. Surveillance should be risk-based and not dependent on who develops the test.

Exemptions

The risk-based approach and feedback that the FDA received to its “notification” led to some LDTs being exempted from the FDA's surveillance, including for example:

• Low risk LDTs;
• LDTs for rare diseases;
• LDTs intended solely for forensic use.

And other exemptions.

d) Summary of the legal requirements

Almost all requirements found in the IVDR already existed in the same or a similar way within the framework of the MPG and the associated ordinances.

Although the new Annex I of the IVDR is longer than Annex I of the IVDD, the key elements still include:

• Risk management
• A safe and powerful device design
• Usability,
• Performance evaluation
• software life cycle processes

IT security is a major new requirement.

Exemptions from surveillance for certain LDTs (e.g. LDTs for the diagnosis of rare diseases), as implemented by the FDA, are currently not planned.

4. Transitional periods

In January 2022, new transitional periods were included in the IVDR, which also addresses the requirements of Article 5 (5) and thus affect in-house IVDs.

Change history

• 2023-01-12:
  • Adaptation of the definition "In-house device" according to the new MDCG 2023-1.
  • Reference to MDCG 2023-1 and slight adjustments in section 3. b)
  • Reference to MDCG 2023-1 in section 5.
• 2022-12-09: Notes on the revision of ISO 15189 added
• 2022-06-08:
  • Conversions due to the IVDR which has become valid.
  • "LDT" replaced by "In-house IVD", the official wording of the EU
  • Adjustments due to the transition periods
  • Removal of section 3 e) "Effects of the ongoing coronavirus pandemic"

• 2021-04-22: Section 3. e) on the effects of the ongoing coronavirus pandemic inserted. Editorial changes.
• 2021-12-01: Corrections, adjustments to links and editorial changes throughout the article. Adaptation of the sections
  • a): Revision of the definitions
  • b): Restructured
  • 4: New section on transition periods added
  • b): Adaptation to possible new transition periods