Clinical trial protocol design amid evolving global IVD regulations

Regulatory requirements applied to global clinical laboratory testing are currently undergoing a notable period of transition, particularly within the US and EU, due to the FDA LDT Rule¹ and IVDR², respectively. This evolving regulatory environment requires use of in vitro diagnostic (IVD) assays, with an appropriate intended use, in all cases where the result will be used to guide a medical decision for a participant. The intent of course being that review of the assays by the regulatory bodies assures availability of high quality IVD products whose results will enable higher quality medical decisions for participants and better care for patients.

Challenges in IVD development and market considerations

Attempting to gain approval to market an IVD product requires significant investment in time and resources and those who undertake IVD development activities will understandably only do so when there is sufficient commercial demand to facilitate return on investment. A key implication of this is that tests that are infrequently required are less commercially interesting to IVD manufacturers. This issue, coupled with the evolving regulatory environment, notably impacts clinical trial protocol design and places an emphasis on considering availability of IVDs level solutions for those components of the protocol intended to guide a medical decision including but not limited to enrolment, inclusion/exclusion, assignment to treatment arm, monitoring and/or safety and investigation of rare events such as drug induced liver or kidney injuries.

Distinguishing standard clinical IVD tests from non-standard biomarkers

When defining the tests within a protocol that are to be used for the ongoing assessment of safety and protection of participant health, it is important to distinguish standard clinical lab IVD tests needed for medical decision making from non-standard biomarkers that are not supported by available off the shelf IVD solutions. While the latter may be supported by notable peer review studies and various off the shelf Research Use Only [RUO] products, recent changes in lawmaking driven by various global regulators emphasize importance on use of IVD products for tests needed for medical/diagnostic purpose. IVDs are to be expected to have improved quality and better-defined performance when used in accordance with their intended use, as such they are better positioned to protect participant health. Alternate solutions to use of nonstandard RUO biomarkers for medical decision making include structuring the clinical trial protocol such that the test is only used for exploratory purposes, use of an alternate test or test panel that provide comparable information but from IVD level solutions, or, contracting an assay manufacturer to create an IVD level solution.

Inclusion of such tests within the exploratory biomarker section enables advancement of knowledge on its strengths (and weaknesses) while also streamlining safety decisions for clinical site clinicians who will invariably have mixed and often very limited experience of the medical utility of the test. Note also for more niche or complex adaptive drug trial designs, the protocol will need to consider the appropriate regulated status of the assay for each purpose, e.g., “seamless” adaptive trial design that includes both non-/preclinical elements where an RUO assay may be sufficient, with later parts that encompass clinical testing and would require an IVD-classed assay with associated medical purpose. Specifically in the US, a key criteria for medical purpose of an assay is if an invasive biopsy procedure is written into protocol associated with that sample being used for the assay in question.

Leveraging alternative IVD tests and biomarker panels

Where data is needed to guide a medical decision, consideration could be given to addressing the need with a combination of clinical observations and an alternate test or panel of tests that can be performed with IVD-classed assays. For example, use of nucleic acid amplification tests (NAAT) provides a routine and streamline mechanism for detection of Hepatitis Delta Virus (HDV). However, due to very limited prevalence and commercial demand, IVD versions of such tests are challenging to come by and there is no currently approved FDA IVD assay. Alternate IVDs that may be written into protocol that aid understanding of the HDV status of the participant via IVD level solutions include assessments of HBSAg, HBSAB and HDV Ab. Considering the prevalence of HBV in the US (0.4%³) and HDV infection (4.6% of HBV positive participants⁴ ), this panel would be expected to provide a clear cut answer in a vast majority of cases within clinical trial populations. It would not provide certainty on current infection status in participants that are positive for both HBSAG and HDV IgG but negative for protective HBSAB levels. However, the algorithm would avoid use of non-IVD tests that may otherwise draw scrutiny from regulatory bodies while also providing greater certainty, by virtue of use of IVD assays, to clinical sites.

Use of alternate tests or panels that can be performed with IVD level assays, or using a test as an exploratory biomarker, may not always be an option for a clinical trial. For example, enrolment criteria can often be designed to focus on inclusion of individuals with a rare specific trait, e.g., a non-wild type genotype. Historic genotyping data already available within the participants’ file may be written into protocol should the risk associated with use of multiple local methods, that may not produce consistent results from all specimens, be considered acceptable. Alternatively, where it is critical for a study sponsor to have centralised assessment of genotype for trial enrolment, the trial Sponsor may consider contracting custom assay development, manufacture and associated regulatory submission support, e.g., an investigational device exemption (IDE) for the US-FDA. Increased use of this option is expected to occur as a result of the evolving regulatory environment. The timelines and cost associated with the custom creation of such assays solutions is important to consider when designing a clinical trial protocol and defining study milestones. Early engagement with such providers, e.g., ICON Laboratory Solutions, is strongly recommended as it will provide greater certainty on exact requirements and deliverables.

Summary

The currently evolving regulatory environment of clinical laboratory testing creates new challenges, and opportunities for drug developers designing global clinical trials. Global laboratory organisations such as ICON welcome the opportunity to discuss test solutions with the appropriate regulated state that maximise ability to provide high quality analytical data that guide high quality decisions. Contact us for more information.

References

¹Medical Devices; Laboratory Developed Tests, A Rule by the Food and Drug Administration on 05/06/2024 https://www.federalregister.gov/documents/2024/05/06/2024-08935/medical-devices-laboratory-developed-tests

²Regulation (EU) 2017/746 of the European Parliament and of the Council, on in vitro diagnostic medical devices and repealing Directive 98/79/EC and Commission Decision 2010/227/EU http://data.europa.eu/eli/reg/2017/746

³Kim WR. Epidemiology of hepatitis B in the United States. Hepatology. 2009 May;49(5 Suppl):S28-34. doi: 10.1002/hep.22975. PMID: 19399791; PMCID: PMC3290915.

⁴Gish RG, Jacobson IM, Lim JK, Waters-Banker C, Kaushik A, Kim C, Cyhaniuk A, Wong RJ. Prevalence and characteristics of hepatitis delta virus infection in patients with hepatitis B in the United States: An analysis of the All-Payer Claims Database. Hepatology. 2024 May 1;79(5):1117-1128. doi: 10.1097/HEP.0000000000000687. Epub 2023 Nov 16. PMID: 37976395; PMCID: PMC11020024.

Challenges in IVD development and market considerations

Distinguishing standard clinical IVD tests from non-standard biomarkers

Leveraging alternative IVD tests and biomarker panels

Summary

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