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

Laboratory developed tests (LDT) are a type of in vitro diagnostic test. But do regulatory requirements such as the IVDR also apply to these “in-house tests”? This article provides an overview not just for medical laboratories.

1. Why you might have to reduce the range of tests you offer when the IVDR comes into effect in May 2022

The EU legislator is regulating laboratory developed tests for the first time with EU Regulation 2017/746 on In Vitro Diagnostic Medical Devices. 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 is 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. Laboratory developed tests: what are they?

a) Definition of terms

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. Tests developed in-house, known as LDTs

Accordingly, the US authority the FDA defines the term LDT as follows:

The German Medizinproduktegesetz (MPG) calls these tests ‘in vitro diagnostic medical devices from own production.

The IVDR calls LDTs “devices manufactured and used only within health institutions established in the Union”, but does not define the term explicitly.

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

b) Where laboratory developed tests are used

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

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

• Uses procedures it has developed or refined itself
• Uses non-IVD devices in diagnostic procedures (e.g. for research use only, RUO) or
• Uses a CE-IVD device outside its intended purpose (off-label use), e.g., when they:
  • Combine their own procedures with a CE-IVD device 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) Existing requirements for LDTs in Germany

Putting in vitro diagnostic medical devices from own production into service is currently 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 offer an LDT, 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). Alternatively, a lot of laboratories can be accredited according to the international standard ISO 15189.

b) New requirements in the IVDR:

On the one hand, the IVDR wants to continue to permit “in-house” devices without the involvement of notified bodies and without CE marking (whereas 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. These include:

1. The manufacture and use of the devices occur 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.
2. The laboratory of the health institution is compliant with standard EN ISO 15189 or where applicable national provisions, including national provisions regarding accreditation.
   • This is, therefore, not a new requirement since, according to the state of the art, compliance with Rili-BÄK is sufficient here.
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 device on the market no longer have a right to exist.
4. The health institution draws up a declaration which it shall make publicly available, including a declaration that the devices meet the general safety and performance requirements set out in Annex I.
   • This is precisely what has already been required for years by the Medizinprodukteverordnung (MPV Article 5)
5. The health institution reviews experience gained from clinical use of the devices and takes all necessary corrective actions.
   • The MPV also already requires this in article 5.

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 exist 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,
• The performance evaluation
• The 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. Surveillance by authorities

In Germany, the respective Land authorities are responsible for the surveillance of the laboratories. They check whether laboratories are complying with the MPBetreibV and thus explicitly ensure compliance with the Rili-BÄK. If your laboratory is accredited according to ISO 15189, DAkkS is responsible for surveilling your laboratory. For IVD manufacturers, it is the Land authorities and, depending on the class of the device, the notified bodies that are responsible for surveillance.

The assumption that, at least in the case of the Land authorities, the same bodies are responsible for the surveillance of manufacturers and laboratories is not always justified. For example, in Baden-Württemberg, the regional council in Freiburg is responsible for IVD device manufacturers and the regional council in Tübingen is responsible for laboratories.

5. Conclusion

a) The IVDR makes concrete demands of laboratories

Although the MPG already required the essential requirements of Annex I of the IVDD to be met, comprehensive compliance with these requirements was not achieved.

The IVDR now establishes uniform requirements for laboratories across Europe.

• Laboratories must develop, manufacture and surveil their own laboratory developed tests (largely) in conformity with the requirements of the IVDR.
• The use of commercially available IVD devices is preferred and laboratories can only offer their own LDTs if the devices on the market do not offer the required performance.

The previous system was also difficult to understand: why should the regulatory requirements for a laboratory test depend on whether it was developed by a laboratory or an IVD manufacturer?

A lot of medical laboratories are not fully aware of the existing and the new requirements. It’s high time they got busy. Tougher competition between laboratories and legal disputes with IVD manufacturers should be expected.

b) Your next steps as a medical laboratory

It would be best to research the market immediately: look for devices whose performance promises for the same patient target group are the same as for your LDT.

Is there no such device on the market? Congratulations, you can offer your LDT! You should comply with the following requirements:

• Add conditions for production and the new requirements of Rili-BÄK 2019 to your quality management system
• Comply with the additional requirements of Article 5(5) of the IVDR

Add the extended requirements of Annex I of the IVDR

But if there is an equivalent device on the market that offers the same level of performance, you need to urgently think about your strategy for 2022. The Johner Institut will be delighted to provide support.

1. Make a decision:
   1. No longer offer the test
   2. Purchase and use the authorized competitor test or
   3. Place your own test on the market as a CE-IVD device
2. If you decide to place the test on the market as a CE-IVD device:
   1. Establish a QMS according to ISO 13485
   2. Find a notified body
   3. Comply with the extended requirements of the IVDR

(Depending on the risk class of the device) create device-specific technical documentation and declare conformity.