Laboratory Developed Tests LDT

Laboratory Developed Tests (LDT) are included among in vitro diagnostic tests. However, do the same regulatory requirements apply to these LDTs as, for example, to the IVDR? This article provides an overview for medical laboratories, among others.

Medical laboratories, also called specialist laboratories, examine samples taken from the human body, such as bodily fluids (blood, urine, cerebrospinal fluid, etc.) and tissue. In order to obtain diagnoses or information relevant to the diagnosis of these samples the laboratories use:

1. Commercial in-vitro diagnostics
2. Tests developed in-house so-called Laboratory Developed Tests (LDTs)

Accordingly, the FDA defines the term Laboratory Developed Test (LDT) as follows:

a) Requirements for In vitro Diagnostic Medical Devices

Commercial in vitro diagnostics are among the medical devices. Their manufacturers must meet the requirements of the EU directives (IVDD) and EU regulations (IVDR) or must undergo the corresponding approval procedures for IVD at the FDA, such as Premarket Approval (PMA).

Laboratory Developed Tests (LDTs) must be differentiated as to whether they are a product or a process. For a product one would speak of self-production according to §3 MPG [Medizinproduktegesetz: German law on medical devices].

b) Requirements for Medical labs

Medical laboratories are bound by the “Guidelines of the German Medical Association on quality assurance in Laboratory Testing”, or "RiliBÄK Labor" for short in German. To demonstrate compliance with these guidelines, many laboratories are certified to ISO 15189. This standard is entitled "Medical Laboratories - Requirements for Quality and Competence".

Neither RiliBÄK nor ISO 15189 formulate requirements for the development and production of IVD products. The validation of these products is also incompletely specified. Only the quality assurance of the test results is covered by specific requirements. However, these concern implementation rather than the development or production of tests.

c) Requirements in Germany for Laboratory Developed Tests

The DAkkS has published the “Guideline of the Sector Committee Pathology/Neuropathology for the validation of examination methods in Molecular Pathology” with the ID 71 SD 4 037.

This document, in contrast to ISO 15189, specifies at least the validation of the tests. It does not differentiate between analytical and clinical performance. Labs that are aware of this run the risk of only carrying out the validation on an analytical level – in the worst case not even with clinical samples.

d) Requirements of the IVDR

On the one hand, the EU regulation (2017/746) on in-vitro diagnostic devices (IVDR) wants to also permit in-house products in future. It states:

“Health institutions should have the possibility of manufacturing, modifying and using devices in-house and thereby addressing, on a non-industrial scale, the specific needs of target patient groups which cannot be met at the appropriate level of performance by an equivalent device available on the market [...]”

On the other hand, the IVDR is well aware of the risks caused by LDTs. It states:

“To ensure the highest level of health protection, the rules governing in vitro diagnostic medical devices, manufactured and used within a single health institution only, should be clarified and strengthened. That use should be understood to include measurement and delivery of results.”

It therefore limits the ability to make products in-house by declaring:

“Health institutions should have the possibility of manufacturing [...] devices in-house [...]  which cannot be met at the appropriate level of performance by an equivalent device available on the market.” 

Consequently, in Article 5 (5), the IVDR formulates conditions that laboratories that exclusively(!) develop and use in-house tests must fulfil. These include:

• The manufacture and use of the products shall take place within the framework of suitable quality management systems;
• The healthcare institution's laboratory shall comply with the EN ISO 15189 standard or, where appropriate, with national regulations including national accreditation rules;
• The healthcare organisation shall provide in its documentation justification that the specific needs of the patient target group can be met or not at the indicated level of performance by a similar product on the market;
• The healthcare organisation shall make a statement which makes it publicly available and which, inter alia, contains a statement that the products meet the essential safety and performance requirements set out in Annex I;
• The healthcare facility shall review the experience gained from the clinical use of the products and takes any necessary corrective action.

And now the most relevant burden: laboratories must always comply with Annex 1 of the IVDR in an in-house development!
Further requirements apply to class D products.

e) FDA Requirements for Laboratory Developed Tests

At least since 2010, the FDA has been thinking about regulating LDTs. The administration is aware of the risks of incorrect or inappropriate treatment of patients that may result from under-controlled "high-risk LDTs."
The previous "enforcement discretion" no longer considers the authority to be adequate for all LDTs.

Therefore, in 2014, the FDA published "FDA Notification and Medical Device Reporting for Laboratory Developed Tests (LDTs)" as a draft and gathered feedback. This resulted in a "Discussion Paper", which the FDA published in January 2017.

In this document, the FDA states that it finds it problematic that a test developed by an IVD manufacturer is regulated differently than the identical test that a lab has developed. This would undermine the risk-based approach. Monitoring should be carried out depending on the risk and not on who is developing the test.

Principles

In the Discussion Paper, the FDA concludes that the monitoring of LDTs ??should be based on the following principles:

• a risk-based approach to oversight;
• independent premarket review for certain tests and for some modified tests;
• a focus on analytical and clinical validity as the basis for test approval;
• risk classification activities;
• adverse event reporting;
• exemption of certain categories of tests from premarket review;
• a robust laboratory quality system;
• “grandfathering” for tests available prior to a specific date; and,
• public availability of test performance information.

Exceptions

The risk-based approach and feedback received from the FDA on its "Notification" led to the exemption of the following products from FDA surveillance:

• low risk LDTs;
• LDTs for rare diseases;
• traditional LDTs (i.e., tests that use components that are legally marketed for clinical use and whose output is the result of manual interpretation by a qualified laboratory professional, without the use of automated instrumentation or software for intermediate or final interpretation);
• LDTs intended solely for public health surveillance (i.e., intended solely for use on systematically collected samples for analysis and interpretation of health data that are essential to the planning, implementation and evaluation of public health practice, which is closely integrated with the dissemination of these data to public health officials and linked to disease prevention and control);
• LDTs used in CLIA-certified, high-complexity histocompatibility labs to perform allele typing, antibody screening and monitoring, or crossmatching in connection with organ, stem cell, and tissue transplantation; and
• LDTs intended solely for forensic use.

a) Germany

In Germany, the notified bodies or the competent state authorities supervise the manufacturers. At laboratories, it is the DAkkS or the competent state authorities.

The assumption that at least the same authorities are responsible for the supervision of manufacturers and laboratories, at least in the respective state authorities, is not always justified. In Baden-Württemberg, for example, responsibility lies with the manufacturers at the regional council in Freiburg and the laboratories at the regional council in Tübingen.

b) USA

The situation is similar in the USA. The FDA “complains” in the above-mentioned "Discussion Paper" that the different supervisory responsibilities complicate matters: the FDA oversees the IVD manufacturers, while the "Centers for Medicare and Medicaid Services (CMS)" are responsible for monitoring the laboratories.

The times are coming to an end when medical laboratories can develop and produce their laboratory-developed tests largely unaffected by the legal requirements for in vitro diagnostics.
The IVDR commits the laboratories to

• either use commercially available IVD - if available
• or to develop, manufacture, and monitor their own laboratory-developed tests (largely) in compliance with the requirements of the IVDR
• and/or even subject these LDTs ??to a full conformity assessment procedure – even including a notified body, depending on the class.

It has also been difficult to understand the current practice: why should the regulatory requirements for a laboratory test depend on whether it is developed by a laboratory or an IVD manufacturer?

Many medical laboratories are not yet fully aware of the new requirements that await them. It is high time that they dealt with them. Harsher competition between laboratories and litigation with manufacturers are expected.

Note: In the "IVDR seminar" the molecular biologist Sebastian Grömminger PhD gives you a comprehensive overview and shows you how to meet the requirements for in-house developments in the laboratory or how you can (even better) become a manufacturer under the IVDR. Holding all the cards as the market changes through the IVDR in 2022.