Preparing for and

implementing an
in-house test
Preparing for and implementing an in-house test

Learning objectives

• Describe how a laboratory can prepare to design and implement an in-house

test, also known as an in-house device (IHD)
• Outline the typical steps of IHD and in-house assay (IHA) implementation and
identify key questions that must be addressed at each stage of the process

Introduction

Clinical laboratories often use tests developed in-house by research and development
(R&D) departments in their respective health institutions. These tests belong to a unique
subcategory of tests in clinical laboratories. Actual patient testing should be segregated
from research operations, conducted using different platforms, and preferably be
performed in separate laboratory spaces. More specifically, clinical and R&D samples
should not be included in the same run, and instrumentation used for an R&D assay
that is located within the footprint of a clinical laboratory should be clearly labeled for
Research Use Only (RUO) and “Not for clinical testing.” It is preferable to avoid sharing
equipment; but if sharing is necessary, the equipment should be clearly identified as
being for either clinical testing or research use on specific days or at specific times of
operation.

If an R&D test has clinical utility, a laboratory may elect to implement it as an IHD. An
IHD is a diagnostic test designed, validated, and performed in-house by an individual
health institution. The decision to develop an IHD is based largely on the patient
population, requests from healthcare providers, the availability of CE-marked in vitro
diagnostics (CE-IVDs), and the technical expertise in the laboratory.

Regulation and harmonization

The European Union (EU) In Vitro Diagnostic Regulation (IVDR) is the first harmonized
requirement for IVDs manufactured and validated for use by individual health
institutions. The IVDR was published in May 2017 (2017/746), and enforcement began
on May 26, 2022. The IHD regulations can be found in Article 5, paragraph 5 of the
IVDR. In the EU, there is a focus on harmonized standards that are issued by
standardization organizations, not regulatory authorities. However, the four major
components of a regulatory strategy for IHDs include defining the proposed product,
risk-based classification of the device, compliance with conformity elements, and
appropriate regulatory approval. The regulatory pathway for a proposed IHD must begin

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with the health institution stating that it intends to use the IHD for patient care with
proper instrumentation and reagents, although not necessarily CE-IVD marked.
Secondly, an IHD can be combined with reagents or devices that are not CE marked. A
CE-marked IVD could be revalidated for a purpose that is not within the manufacturer’s
original scope. IVD, RUO, or IUO devices and reagents may also be used with an IHD
for IVD purposes.
The Global Harmonization Task Force (GHTF) 2012 definition of an IVD was recently
updated by the International Medical Device Regulators Forum (IMDRF) to include risk-
based classification, which requires more specific documentation for Class D devices.
EU member states are allowed to apply risk-based provisions to Class A, B, or C
devices as well. However, questions remain regarding the EU IVDR and its
implementation. For example, the scope of IHDs, the required extent and quality of IHD
risk management systems, comparisons with CE-marked IVDs that would be deemed
acceptable, and the performance evaluation and documentation requirements for IHDs
are unclear.

No explanation from the Medical Devices Coordination Group (MDCG) is currently

available, but European Medical Devices Documents (MEDDEV) documents 2.14/1 and
2.14/2 related to IVD interpretation consider RUO products and devices manufactured
and used by individual health institutions for patient care to be in separate categories.
MEDDEV concluded that RUO products must have no intended medical purposes or
objectives. In contrast, IHD devices are intended for clinical use by health institutions.
This even applies to IHDs originally labeled for RUO or performance evaluation
purposes only by the manufacturers. EU member states have the right to create national
provisions, but these are not uniform across Europe. Laboratories are left to determine
the best strategy for satisfying institutional, regional, and national requirements for
health institutions.

Although an IHD can only be used by the health institution that develops it, a laboratory
may consider developing an IHD the best option when a diagnostic test is needed to
meet specific clinical requirements. It is often the case that no commercial CE-IVD assay
is available to test for a rare disease or genetic condition. A laboratory may also opt for
an IHD when there is a newly identified or newly reported marker that is not included in
the panel of an existing CE-IVD assay. For the sake of clarity, health institutions will be
required to justify the use of IHDs and explain how they are more beneficial than existing
IVDs after 2028, regardless of the rarity or uniqueness of a disease or condition. An IHD
must be verified by demonstrating that it has clinical utility for the intended patient
population, but it can be implemented quickly for emergency use. This is an important
advantage when a test must be developed and deployed in response to an emergency
like an epidemic or pandemic.

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How are IHDs developed?

The need for an IHD is justified based on clinical input to improve patient care. Input
from a clinical advocate is thus key in the assay development process. The laboratory
that develops the assay must be knowledgeable about how the test will be used and
understand the specimen type, range of detection, turnaround time requirements, and
potential complementary tests. It is also advisable to survey the market for any
commercial test that may cover the identified need. The IVDR requires laboratories to
document and publish their justifications for use under the premise that there are no
commercial CE-IVD assays that meet the stated clinical needs. The IVDR also requires
justification for using an IHD instead of an existing IVD, such as greater accuracy or
faster results. The justifications provided must be linked with health benefits over and
above the existing tests.

Health institutions should establish procedures to document their justifications for

developing and using IHDs by continuously monitoring the market for new IVDs that
may satisfy their clinical needs. This creates a level of uncertainty for IHD developers, as
they could spend a substantial amount of money developing tests and be unable to use
them if commercial versions become available. This may make laboratories more
cautious about developing IHDs.

It is at this early stage when a laboratory decides on the technology, specimen type, and
test methodology for the IHD. Test methodology might be as simple as adding a new
analyte to an established test or using a different platform in the laboratory. IHD
methodology could require more intensive development if it involves a new specimen
type, new instrumentation, or new biomarkers. It may also require optimization to
improve sensitivity, reduce turnaround time, or benefit a new patient demographic. A
clinical laboratory in a health institution can develop an IHD for a new analyte or
biomarker(s) de novo and take it through the necessary analytical, performance, and
clinical validation studies as long as it meets the IVDR standards for qualification and
demarcation, risk-based classification, compliance with conformity assessments, and
regulatory compliance.

A health institution can take one of several approaches to develop an IHD. A

combination of CE-marked devices and unmarked devices could be used to create a
new IVD system. If a CE-marked IVD is to be used outside of the vendor’s product
specifications, development of an IHD would also be appropriate. Finally, the use of
unmarked RUO and IUO laboratory products is acceptable if the

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manufacturers of the products have appropriate documentation and ISO quality
management systems.

Deploying an IHD requires a development process that documents standard operating

procedures (SOPs) for the assay and includes basic analytical validation studies to show
that the assay satisfies clinical requirements. It may also include pilot clinical studies to
document the range of values that can be expected in the target patient population.
Validations often follow guidelines from the Clinical and Laboratory Standards Institute
(CLSI), which develops standards for global best practices for medical laboratories.
Handoff to a clinical testing department should include a validation report that provides
direction for the laboratory to verify their SOPs or validate modified SOPs.

Licensure and certification

While any health institution can develop an IHD, a testing laboratory must ensure that
the requirements in Annex I of the IVDR are met and provide a declaration of conformity
to the Competent Authority if requested. Although IHDs and IHAs are largely exempt
from full compliance with the IVDR, Article 5.5 still applies and must be considered.

Quality management and documentation

A clinical laboratory that provides testing for patient diagnosis and monitoring must have
an appropriate quality management system (QMS) according to IVDR Article 5 (5). This
can generally be met by obtaining ISO 15189 accreditation with any additional
documented procedures for the vendor’s manufacturing process covered by ISO 13485.
Some hold ISO 15189 certification by an accreditation body and they may establish
additional procedures to cover the 'manufacturing process' which is not included under
ISO15189. The required QMS applies to all tests, including IVD tests and IHDs. The
QMS encompasses all SOPs; quality control (QC) monitoring; temperature records;
personnel training and competency records; minutes from quality management meetings
with the laboratory director; communications from vendors regarding recalls or changes
in performance; and corrective and preventative action (CAPA) documentation.

Personnel who perform test development do not need to be licensed technologists, but
those who validate or verify IHDs should be trained and qualified to perform testing on
patient specimens and have national licensure in countries where it is required. Once a
test has been validated and the validation report is signed by the laboratory director, all

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technologists who may perform testing must be trained. Competency must be assessed
and documented in the QMS before the technologists are qualified to perform the new
test on patient specimens.

All equipment, testing instrumentation, and reagents must be specified by vendor,

model, serial number, lot number, or other applicable category in laboratory records.
These specifications should not be modified after IVD verification or validation of an IHD
without an impact assessment. The impact assessment should determine whether
additional studies are needed. Since IVD reagents are packaged in kits, reagents from
different lots and non-kit reagents should not be mixed or used for patient testing.

An item labeled for performance evaluation should only be used in a specific study to
establish the performance of an IHD for an intended clinical purpose. It should not be
used for diagnostic purposes, and registration in an EU database is required for
performance evaluation studies. RUO devices are not generally made under ISO
13485, and the IVDR does not stipulate that RUO items used for in-house assays have
to be manufactured under ISO 13485. The IVDR states that the manufacture of IHDs
themselves must be done under an appropriate QMS, but it does not provide details
about how reagents used for manufacturing must be manufactured. It would depend on
the reagents and their impact on the performance of the IHDs. All reagent specifications
and documentation should be provided by the vendor and retained as laboratory
records. A reagent from a new lot must be tested in parallel with an equivalent reagent
from an old lot for both IVD tests and IHDs, and documentation of acceptable
performance must be signed by the laboratory director.

If a different testing platform is selected for an existing IHD, a parallel study must be
performed to compare performance on the old and new platforms. For example, a
laboratory may develop an IHD using a technology platform that is readily available in
the laboratory, such as conventional PCR, and additional PCR platforms may be
qualified by parallel testing.

Proficiency requirements

All laboratories can use outside comparative studies to demonstrate the clinical utility of
their IHDs. These can be clinical utility studies, proficiency testing performed by certified
vendors, or previous testing of repeat clinical samples. Requirements for proficiency
testing should be considered in Asia-Pacific countries, the US, and Australia. National
standards and practices should be adhered to in the EU.

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Remnant samples should be added blindly to the laboratory testing queue at least twice
per year, and they must have proven stability at the archiving temperature. Depending
on national restrictions, patient consent may not be required for the use of remnant
samples in test validation and parallel studies if the samples have previously been
reported and could have been discarded.

Personnel training documentation

IVD tests and IHDs share the same regulatory requirements for documenting results.
Depending on national and institutional policies, all SOPs must be reviewed and signed
by the laboratory director to document any updates. Any changes or updates can be
reviewed off cycle or during a required review timeframe. Changes and updates may
necessitate retraining and documentation of retraining as well as competency
assessments for all testing personnel.

The QMS will require that all previous versions of documents and results be archived
and available for retrieval when needed. All software integrated with the laboratory
information system (LIS) must safeguard protected health information (PHI) and ensure
patient confidentiality under the EU General Data Protection Regulation (GDPR), which
is similar to the US Health Insurance Portability and Accountability Act (HIPAA). The
GDPR is broader in scope than the HIPAA and applies to sensitive personal data as
well as data concerning health. Most LISs are designed to trace access by everyone
who logs into a test workflow and provide audit trails. Security levels are determined
before the software is implemented in the laboratory and maintained to prevent
unauthorized access.

Implementing an IHD

How does a health institution implement an R&D assay as an IHD? There are multiple
steps in the decision-making process leading to the launch of an IHD. Technical and
legal feasibility must be evaluated first. The laboratory director and clinical advisors
should draft a development plan to determine the design of the assay along with its
intended use and performance specifications. IVD product specifications for assays that
have similar clinical applications should be compared to the expected performance of
the IHD. Article 5.5 (d) states that use of an IHD is permissible when an IVD exists if the
health institution establishes that the specific needs of the target patient group cannot
be fulfilled adequately with an equivalent device on the market. The IHD testing
technology and platform should be suitable for the assay as designed. It is equally
important to determine whether the platform is already available in the clinical
laboratory.

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Feasibility and design assessment

Figure 1 illustrates the steps of IHD implementation. Key parameters include the reason
for developing the test, how it is performed, and how it fits into laboratory operations.
Implementation in a clinical laboratory must be feasible in terms of the space, airflow,
and technological training it will require. Once the testing procedure is optimized, the
test must be analytically validated according to requirements. These include
requirements for accuracy, sensitivity, specificity, reproducibility, and other parameters
that will depend on the sample source and technology involved.

Figure 1. Typical IHD implementation process from planning to launch.

The path from development to launch

How long does it take to develop and validate an IHD for clinical use? Depending on the
technology, it can take up to 12 months to complete all phases. Once the technology
has been established in the project planning phase, the test platform must be qualified
for use and available to the development team. The testing procedure must be
developed and optimized, and reagents, calibrators, controls, and consumables must be
identified, ordered, and placed in inventory.

Depending on the technology, calibrators and controls for molecular IHDs may be
purchased from IVD or RUO vendors or prepared in-house from purified reagents
spiked into appropriate matrices. Primers and probes selected for genetic sequence
analysis must be tested for specificity and confirmed by BLAST™ analysis. DNA and

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RNA extraction reagents can be purchased and optimized for a given sample matrix if
necessary. PCR master mixes may be commercially available or developed in-house. In
all cases, documentation of validation testing must be retained, organized, and available
for review.

Reagents used with an IHD must meet the quality requirements of the laboratory. If they
are purchased from vendors who also provide IVD kits, they would be considered IHD
reagents rather than IVD reagents. When laboratories use such reagents with their
IHDs, the IHDs must also meet the specified accuracy requirements.

After the project planning phase, an IHD assay must be optimized and analytically
validated for accuracy, sensitivity, specificity, and reproducibility just as it would in an
IVD analytical validation study. All testing procedures should be well documented and
meet the IVDR general safety and performance requirements (GSPRs) outlined in
Annex I. SOPs for an IHD must be specific and updated regularly to meet national and
institutional requirements, and documentation must show that the SOPs have been
followed appropriately. An IHD laboratory must document all analytical validation and
clinical utility studies as well as the performance of assay controls within specified QC
ranges.

Although IVD assay and IHD development both require project planning, instrument
identification and qualification, staff training, and pre-validation planning, the analytical
validation period can be quite variable. Analytical validation of an IHD often takes longer
due to limited technical resources. IVD tests are clinically validated by the vendors with
samples from a wide range of patients, while the availability of samples at individual
health institutions may be limited. Clinical validation of an IVD test can overlap with
analytical validation, but specific clinical specimens must be analyzed to verify the
usefulness of an IHD for patients. Clinical verification of an IHD is less stringent than
IVD validation; although, this will depend on the availability of specimens from patients
with and without the disease of interest and the presence or absence of the target
analyte in patient samples.

Conclusion

IHDs have a specific role in clinical laboratories. As a single-site test, an IHD is owned
by the health institution that develops it. For legal reasons, intellectual property and the
freedom to operate should be established prior to IHD development. A laboratory that
designs an IHD must consider which testing platforms are available as well as the
clinical need the test will fulfill. For example, an IHD designed for a highly sensitive

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chemical analysis might require a new platform. A blood test for molecular identification
of a new parasite might be adapted from a urinalysis assay.

Every clinical laboratory should have an appropriate QMS, such as an ISO 15189 QMS,
and IHDs must satisfy laboratory QMS requirements. Clinical laboratories should also
maintain training and competency documentation for all employees. All IHD analytical
validation studies must document the accuracy, sensitivity, specificity, and
reproducibility of testing when applicable. The IVDR states the need to evaluate and
document analytical and clinical performance, and the types of studies required are
listed and noted in the IVDR when applicable. Clinical verification studies are also
required for IHDs to show that the tests have clinical utility for the target populations
defined by the testing laboratory.

References

1. Medical Laboratories—Requirements for quality and competence (ISO

15189:2012).
2. Medical Devices—Quality management system—Requirements for regulatory
purposes (ISO 13485:2016).
3. International Medical Device Regulators Forum. Principles of In Vitro Diagnostic
(IVD) Medical Devices Classification. IMDRF/IVD WG/N64FINAL:2021 (21
January 2021).
4. Spitzenberger F, Patel J, Gebuhr I, Kruttwig K, Safi A, Meisel C (2022)
Laboratory-developed tests: design of a regulatory strategy in compliance with
the international state-of-the-art and the Regulation (EU) 2017/746 (EU IVDR [In
Vitro Diagnostic Medical Device Regulation]). TIRS 56:47–64.

Authors

Mara G. Aspinall, MBA, Managing Partner, Health Catalysts Group; Professor of

Practice and Co-Founder Biomedical Diagnostics Program, Arizona State
University

Michael Donovan, PhD, JD, Managing Partner, MJD Consulting; Lecturer,

Biomedical Diagnostics, Arizona State University

Marilyn Owens, PhD, MBA, Managing Partner, Medical Laboratory Strategy and
Leadership, LLC