National foreword

This British Standard is the UK implementation of EN ISO 5649:2024. It is identical to ISO 5649:2024.

The UK participation in its preparation was entrusted to Technical Committee CH/212, IVDs.

A list of organizations represented on this committee can be obtained on request to its committee manager.

Contractual and legal considerations

This publication has been prepared in good faith, however no representation, warranty, assurance or undertaking (express or implied) is or will be made, and no responsibility or liability is or will be accepted by BSI in relation to the adequacy, accuracy, completeness or reasonableness of this publication. All and any such responsibility and liability is expressly disclaimed to the full extent permitted by the law.

This publication is provided as is, and is to be used at the recipient’s own risk.

The recipient is advised to consider seeking professional guidance with respect to its use of this publication.

This publication is not intended to constitute a contract. Users are responsible for its correct application.

Compliance with a British Standard cannot confer immunity from legal obligations.

This British Standard was published under the authority of the Standards Policy and Strategy Committee on 31 December 2024.

Foreword

ISO (the International Organization for Standardization) is a worldwide federation of national standards bodies (ISO member bodies). The work of preparing International Standards is normally carried out through ISO technical committees. Each member body interested in a subject for which a technical committee has been established has the right to be represented on that committee. International organizations, governmental and non-governmental, in liaison with ISO, also take part in the work. ISO collaborates closely with the International Electrotechnical Commission (IEC) on all matters of electrotechnical standardization.

The procedures used to develop this document and those intended for its further maintenance are described in the ISO/IEC Directives, Part 1. In particular, the different approval criteria needed for the different types of ISO documents should be noted. This document was drafted in accordance with the editorial rules of the ISO/IEC Directives, Part 2 (see www.iso.org/directives).

ISO draws attention to the possibility that the implementation of this document may involve the use of (a) patent(s). ISO takes no position concerning the evidence, validity or applicability of any claimed patent rights in respect thereof. As of the date of publication of this document, ISO had not received notice of (a) patent(s) which may be required to implement this document. However, implementers are cautioned that this may not represent the latest information, which may be obtained from the patent database available at www.iso.org/patents. ISO shall not be held responsible for identifying any or all such patent rights.

Any trade name used in this document is information given for the convenience of users and does not constitute an endorsement.

For an explanation of the voluntary nature of standards, the meaning of ISO specific terms and expressions related to conformity assessment, as well as information about ISO's adherence to the World Trade Organization (WTO) principles in the Technical Barriers to Trade (TBT), see www.iso.org/iso/foreword.html.

This document was prepared by Technical Committee ISO/TC 212, Medical laboratories and in vitro diagnostic systems, in collaboration with the European Committee for Standardization (CEN) Technical Committee CEN/TC 140, In vitro diagnostic medical devices, in accordance with the Agreement on technical cooperation between ISO and CEN (Vienna Agreement).

Any feedback or questions on this document should be directed to the user’s national standards body. A complete listing of these bodies can be found at www.iso.org/members.html.

Introduction

Medical laboratory testing is carried out to an appropriate standard and all work is performed with a high level of skill and competence so as not to produce unreliable results which can lead to patient harm.

In many medical laboratories, the majority of routine clinical samples are processed and analysed using commercially available tests on automated instrumentation purchased from various manufacturers of in vitro diagnostic (IVD) medical devices. The marketing of medical devices is usually regulated by national bodies, and devices must undergo stringent assessment before they can be placed on the market and put into service.

However, there are clinical indications for which there are no commercially available IVD medical devices for the specific intended use or there is a requirement for adding additional specification/approach(es) to a commercial IVD medical device. Such tests are referred to as laboratory-developed tests (LDTs). LDTs can be defined as tests developed (or modified) and used within a laboratory to carry out testing on specimens, such as blood, body fluids and tissues, and samples derived from human specimens, such as bacterial isolates, where the results are intended to assist in clinical diagnosis or be used in making decisions concerning clinical management.

Due to technological development, advanced examinations are continuously introduced in the medical laboratory. These can include, but are not limited to liquid chromatography-tandem mass spectrometry (LC-MS/MS), time-of-flight/mass spectrometry (TOF/MS), nuclear magnetic resonance (NMR), molecular diagnostic testing (e.g. polymerase chain reaction (PCR) based and next generation sequencing (NGS)), in situ hybridization (ISH), immunohistochemistry (IHC), whole slide scanning and imaging, algorithm-based analyses and other emerging technologies. These techniques may be developed in a clinical research laboratory, transferred to the medical laboratory, and placed into routine use as diagnostic tests without going through the same standard approval processes as commercially available IVD medical devices. These tests are also considered to be LDTs.

LDTs have become more complex because of available technology and are increasingly being used to diagnose high-risk conditions such as cancer, genetic disorders, rare diseases, etc., which in turn highlights the need to ensure that the results obtained are accurate and reproducible to safeguard the health and well-being of patients. While many laboratories can perform validation studies of these tests, there is currently no international standard by which to assess the rationale for their intended use, design, development, performance, quality, and reliability.

This document is intended to be used to provide additional guidance to laboratories using LDTs. Accreditation to ISO 15189 is not a pre-requisite for laboratories to use this document.

Conceptually, the lifecycle of an LDT involves sequential phases that extend from the feasibility assessment to the final retirement of the examination procedure. The main phases of a typical LDT lifecycle described in this document, therefore, include the feasibility assessment, the design and development phase, the preliminary/pilot testing followed by the performance evaluation phase, including validation and the verification phases, the monitoring and review activities during LDT use, and the final retirement of the LDT. The illustration shown in Figure 1 below demonstrates these different phases and indicates which clauses of this document cover the corresponding lifecycle phases for an LDT. The arrows back to previous phases within Figure 1 indicate an iterative, dynamic process which can include look-backs, rework or revalidation for improvement of the LDT.

The rationale for the use of an LDT and the feasibility assessment consider the demand for an LDT and determine whether analytical and clinical performance of the new LDT can meet requirements for adequate measurement procedure results (refer to 4.1 and 4.2 of this document).

Design and development include the planning and definition of formal specifications for LDT performance including iterative improvement of all LDT components according to the intended use of the LDT. This can include redesign and reassessment of feasibility and the formal specifications of the LDT as a dynamic process covering all aspects of the LDT development (refer to 5.1 to 5.3 of this document).

Preliminary testing precedes the performance evaluation phase and determines the technical aspects of the LDT by demonstrating that the LDT meets the design and development requirements (refer to 5.4 of this document).

Performance evaluation includes the collection, analysis and assessment of performance data typically generated from validation and verification studies, but also includes activities of risk management and supports the demonstration of the conformity of the LDT to applicable principles of safety and performance.

Validation is a defined process to confirm and control that the finally designed and developed LDT is suitable for its intended use and fulfils all analytical and clinical performance claims (refer to 6.2 to 6.7 of this document).

LDT specifications are verified, where relevant aspects of the LDT procedure deviate between the phase of validation and routine use of the LDT (refer to 6.8 of this document for verification).

LDTs are continuously monitored and periodically reviewed to ensure conformity with the original performance specifications. Significant changes of the LDT require a restart of the processes affected by the modification including revalidation (refer to 7.1 to 7.5 of this document for implementation and monitoring).

LDTs that need replacement shall be retired (refer to 7.6 of this document for retirement).

An example for how this lifecycle can be applied to a workflow is presented in Annex A of this document.

This European Standard was approved by CEN on 6 December 2024.

CEN members are bound to comply with the CEN/CENELEC Internal Regulations which stipulate the conditions for giving this European Standard the status of a national standard without any alteration. Up-to-date lists and bibliographical references concerning such national standards may be obtained on application to the CEN-CENELEC Management Centre or to any CEN member.

This European Standard exists in three official versions (English, French, German). A version in any other language made by translation under the responsibility of a CEN member into its own language and notified to the CEN-CENELEC Management Centre has the same status as the official versions.

CEN members are the national standards bodies of Austria, Belgium, Bulgaria, Croatia, Cyprus, Czechia, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Netherlands, Norway, Poland, Portugal, Republic of North Macedonia, Romania, Serbia, Slovakia, Slovenia, Spain, Sweden, Switzerland, Türkiye and United Kingdom.

European foreword

This document (EN ISO 5649:2024) has been prepared by Technical Committee ISO/TC 212 "Medical laboratories and in vitro diagnostic systems" in collaboration with Technical Committee CEN/TC 140 “In vitro diagnostic medical devices” the secretariat of which is held by DIN.

This European Standard shall be given the status of a national standard, either by publication of an identical text or by endorsement, at the latest by June 2025, and conflicting national standards shall be withdrawn at the latest by December 2027.

Attention is drawn to the possibility that some of the elements of this document may be the subject of patent rights. CEN shall not be held responsible for identifying any or all such patent rights.

Any feedback and questions on this document should be directed to the users’ national standards body/national committee. A complete listing of these bodies can be found on the CEN website.

According to the CEN-CENELEC Internal Regulations, the national standards organizations of the following countries are bound to implement this European Standard: Austria, Belgium, Bulgaria, Croatia, Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Netherlands, Norway, Poland, Portugal, Republic of North Macedonia, Romania, Serbia, Slovakia, Slovenia, Spain, Sweden, Switzerland, Türkiye and the United Kingdom.

Endorsement notice

The text of ISO 5649:2024 has been approved by CEN as EN ISO 5649:2024 without any modification.

1 Scope

This document establishes requirements for assuring quality, safety, performance and documentation of laboratory-developed tests (LDTs) as per their intended use for the diagnosis, prognosis, monitoring, prevention or treatment of medical conditions.

It outlines the general principles and assessment criteria by which an LDT shall be designed, developed, characterized, manufactured, validated (analytically and clinically) and monitored for internal use by medical laboratories.

The scope includes regulatory authority approved IVD medical devices that are used in a manner differing from approved labelling or instructions for use for that device (e.g. use of a sample type not included in the intended use, use of instruments or reagents not included in the labelling).

While this document follows a current best practice and state-of-the art approach, it does not provide specific details on how to achieve these requirements within specific disciplines of the medical laboratory nor specific technology platforms.

This document does not specify requirements for examination procedures developed by research or academic laboratories developing and using testing systems for non-IVD purposes. However, the concepts presented in this document can also be useful for these laboratories.

This document does not apply to the design, development and industrial production of commercially used IVD medical devices.

2 Normative references

3 Terms and definitions

4 General requirements

4.1 Rationale for laboratory-developed tests (LDTs)

4.2 Feasibility assessment

4.3 Management system

5 Requirements for the design and development of laboratory-developed tests (LDTs)

5.1 Determination of LDT performance specifications

5.2 Risk management

5.3 Essential principles for safety and performance

5.4 Preliminary and pilot testing

6 Requirements for the performance evaluation of laboratory-developed tests (LDTs)

6.1 Performance evaluation

6.2 Validation master plan

6.3 Analytical performance

6.4 Clinical performance

6.5 Excluded performance characteristics

6.6 Software verification and validation

6.7 Validation documentation and final acceptance criteria

6.8 Post validation activities of verification

7 Implementation, monitoring and retirement of laboratory-developed tests (LDTs)

7.1 Transfer into routine use

7.2 Result reporting and interpretation

7.3 Maintenance

7.4 Monitoring and review activities

7.5 Change management

7.6 Retirement of laboratory-developed tests (LDTs)

Bibliography

BS EN ISO 5649:2024

Medical laboratories. Concepts and specifications for the design, development, implementation, and use of laboratory-developed tests

Current

Published:

31 Dec 2024