The impact of companion diagnostic testing on medical decision making and IVD regulations

KEYWORDS:

• Companion diagnostics
• in vitro diagnostics
• FDA
• EMA
• precision medicine

1. Introduction

An increasing number of clinical diagnostic tests are used to inform medical decisions, including the results of companion diagnostic (CDx) testing. In recent years, the importance of these assays has increased, particularly for the treatment of patients with hematological and oncological conditions. By August 2023, more than 60 drugs or drug combinations had an FDA-approved CDx test attached for use [1]. The Food and Drug Administration (FDA) defines a CDx test as an in vitro diagnostic device that provides information that is essential for the safe and effective use of a corresponding therapeutic product [2]. This definition is also reflected in the new In Vitro Diagnostic Regulation (IVDR) for the European Union (EU) and the IVD regulations of several other countries [1,3]. A CDx test is intended to inform drug treatment by directing the physician to choose a certain drug based on the patient’s molecular makeup, and here the assay validity can have a decisive impact on the therapeutic decisions. A false positive test result may lead to unnecessary medical intervention with incorrect medication, resulting in delayed treatment with the appropriate therapy. Conversely, a false negative test result may result in disease progression and, in some instances, prevent patients from receiving the appropriate treatment. The consequences of false positive or false negative CDx test results can be substantial and, in some situations, life-threatening [4].

For decades, the safety and efficacy of drugs have been the responsibility of the regulatory medical agencies. In the US, the FDA, and for the EU, the European Medicines Agency (EMA), and the national competent authorities. In contrast, the regulations for in vitro diagnostics (IVDs) have been more inconsistent and diverse. In the US, a CDx test manufactured by a commercial company for use by other entities such as laboratories and healthcare providers, is regulated by the FDA. However, for laboratory-developed tests (LDT), the situation is different, as they are not overseen by the FDA; instead, they must meet the requirements of the Clinical Laboratory Improvement Amendments (CLIA) [4]. In the EU, IVDs were regulated by the IVD Directive until 2022, and a CDx test was considered low-risk general IVD that could be distributed without any involvement or review by regulators [5]. Through a self-certification procedure, the manufacturer performed a conformity assessment according to the IVD Directive, after which a CDx test could be CE-IVD labeled and distributed. Owing to the central role of IVDs in the treatment decision process, regulations in both the US and the EU are currently undergoing changes. In this editorial, these changes and their background are briefly discussed.

2. CDx test quality

It is of utmost importance that the CDx tests used for making treatment decisions possess sufficient sensitivity and specificity and that the results generated are reliable with regard to accuracy and precision [6]. Before a CDx test can be used clinically, it must undergo intensive analytical and clinical validation and fulfill strict acceptance criteria. However, this does not appear to be the case for all tests used in the clinic to inform treatment decisions, particularly for some LDTs.

Approximately 25% of all CDx tests are based on immunohistochemistry (IHC), which can be hampered by high error rates [1,7–10]. In clinical trials, patients are often tested locally with an LDT for inclusion, and the paraffin tissue blocks are sent for subsequent central testing to verify the local test results. Disagreement rates between 20% and 30% have often been reported, and in a few cases even higher, when local and central test results are compared [7]. Furthermore, proficiency surveys on HER2 testing have shown that commercial FDA-approved assays have a higher acceptance rate compared to LDTs [7,8]. Based on data from 1703 HER2 tests performed, NordiQC estimated the false negative rate for LDTs to be 25% compared to 11% for FDA-approved tests. Similarly, the false positive rate for LDTs was 5%, whereas it was 0% for the FDA-approved tests [9]. Recently, HER2-targeted therapy has been expanded to include HER2 low breast cancer, which is defined as IHC1+ or IHC2+ and negative for HER2 amplification [11]. However, the distinction between IHC0 and IHC1+ appears to be a source of difficulty, with a high discordance rate among pathologists, which may lead to misclassification of patients and incorrect treatment decisions [10].

IHC is not the only CDx platform that is burdened by analytical errors. A publication by the FDA reported several cases of inaccurate or unreliable LDTs that could potentially harm patients [12]. In this report, they describe a LDT real-time polymerase chain reaction (PCR) assay to detect HER2 status in women with breast cancer to guide HER2 targeted therapy. However, owing to the poor sensitivity of the assay, a high false negative rate was observed, resulting in patients not receiving treatment with trastuzumab. A second case in the report also involved a PCR assay to detect the V600E BRAF mutation in melanoma to identify patients for treatment with vemurafenib. The laboratory claimed that the LDT had a higher sensitivity than the alternatives; however, documentation supporting this claim was lacking, which could result in patients being inappropriately administered vemurafenib [12].

In recent years, several reports have highlighted the high variability of LDT next-generation sequencing (NGS) assays [13–15]. One study focused on the KRAS and NRAS genes, which are important in selecting colorectal cancer patients who may benefit from treatment with panitumumab and cetuximab [13]. Nineteen different laboratories tested both wet and dry samples, and seven (37%) correctly reported all variants, three (16%) had fewer than five errors, and nine (47%) had more than five errors. Most of the errors were related to false negative test results. Another study examined variability across 16 different local laboratories in the US and Europe, in relation to the use of NGS for measuring tumor mutational burden (TMB) used to identify patients with solid tumors who may benefit from treatment with the immune checkpoint inhibitor pembrolizumab [14]. This study showed that the use of different NGS platforms resulted in substantial variability in TMB among laboratories, potentially leading to incorrect treatment decisions. Finally, a third study found a substantial discordance of more than 70% between two CLIA-certified laboratories when testing identical patient samples for actionable tumor mutations using different NGS panels [15].

3. Regulatory response

The regulatory response to LDTs in both the US and EU has been to tighten regulations for these types of assays, including CDx tests used for patient stratification, even though not all LDTs exhibit the same level of poor performance, as described above [3,4]. In the US, CDx tests manufactured by commercial companies are mainly classified as high-risk Class 3 medical devices and require formal approval through the submission of a premarket approval (PMA) or 510(k). For this type of IVDs, the FDA conducts a scientific and regulatory review of the documentation to evaluate the performance of the CDx tests to ensure that they generate results with high accuracy and precision [2,4]. According to the FDA, an LDT is an in vitro diagnostic test that is manufactured and used in a single laboratory [16]. These laboratories are certified by the CLIA program, which means that analytical validity must be documented for the assay. However, there are no CLIA requirements in terms of clinical validity [17]. In the US, LDTs constitute a large part of all CDx tests used in the clinic, and for the HER2 assays, it is estimated that up to 20% yield inaccurate results [12]. To ensure the quality of LDTs, in October 2023, the FDA proposed amending its regulations to include this type of IVDs under the Federal Food, Drug, and Cosmetic Act. The new regulations, if passed by the US lawmakers, will be implemented over a five-year phaseout period and are expected to be in effect by 2028 [4].

As previously mentioned, the process for regulating IVDs, including CDx tests, in the EU has, until recently, been quite different from that in the US. Previously, all CDx tests were classified as low-risk general IVDs, and were not subjected to any formal review by regulators [5]. However, with the implementation of the new IVDR, CDx tests will now be classified as moderate-to-high-risk Class C devices, and their performance documentation must be reviewed by a notified body and EMA or National Competent Authorities before being distributed and used by clinical laboratories [3]. By December 2028, all CDx tests used by clinical laboratories must be CE-IVDR labeled, and LDTs will no longer be an option, except in a few special situations.

4. Laboratory developed tests – pros and cons

Although some LDTs have quality issues, they also offer benefits that should not be disregarded when introducing new regulations. For instance, LDTs provide flexibility in meeting specific patient needs, particularly in relation to experimental treatment and ‘off-label’ use. Additionally, LDTs can be developed and implemented faster than the FDA-approved assays. However, the downside of this rapid development may be a compromised validation process. Unlike the FDA-approved CDx tests, LDTs do not require clinical validation, which means that there is no assessment of how well the test performs under clinical conditions. Although clinical validation is time-consuming, it is critical for the CDx tests. Furthermore, there might be a tendency for diagnostic companies to update FDA-approved tests more slowly when new improved technologies emerge compared to LDTs, as this will require review by regulators. Additionally, developing and employing LDTs may be more cost-effective than using FDA-approved assays. Finally, it has been stated that the new regulations could impact innovation and research, as developing LDTs allows laboratories to explore new methodologies and diagnostic approaches. However, it is essential to emphasize that the advantages of LDTs must not compromise the quality of the tests, which seems to have been the case in some situations.

5. Conclusion

Although it has been stated that the new regulations would reduce patients access to clinical tests and hinder the development of novel diagnostics, it is important to remember the findings from the US and EU that highlight the inconsistent quality of LDTs, which will lead to stricter regulations for IVD. Given the pivotal role that CDx tests play in treatment decisions for patients with often life-threatening diseases, it is imperative to minimize the occurrence of incorrect test results. The potential harm caused by false positive and false negative test results can be significant, and the coming changes in regulations must be viewed as measures for improving patient safety.

Declaration of interest

J T Jørgensen has worked as a consultant and advisor for Agilent Technologies, Alligator Biosciences, Argenx, AstraZeneca, Biovica, Visiopharm, and Leo Pharma, and has received royalties from Elsevier. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.