Clinical Researcher—February 2023 (Volume 37, Issue 1)

PEER REVIEWED

Wendy Schroeder, BSN, CRCP, CCRC, ACRP-PM

 

Large and small companies are keen to move new in vitro diagnostic devices (IVDs) to market and will tap into contract research organizations (CROs) and clinical sites to support the clinical validations required for IVD regulatory submissions. IVDs are regulated as medical devices in the United States, but the obligations to demonstrate diagnostic test reliability involve some unique study designs and study implementation technicalities worth reviewing. For example, a safe IVD product will have minimal risks associated with false test results; and an effective IVD will yield meaningful information useful for clinicians to manage patient care and treatment decisions. This limited review highlights compliance obligations and operational logistics associated with IVD clinical performance studies that may prompt sites, sponsors, and CROs to explore talent, update standard operating procedures (SOPs), or edit templates and tools to include the unique aspects of IVD products, study designs, and tactical implementations of IVD clinical trials.

Background

Often, the most exciting studies to offer patients are those that present innovative treatments or technology as an option for disease management. These are the studies most interesting to investigator champions who want access to novel drugs and devices; and the most successful for recruitment when the research offers hope for patients who may otherwise be running out of options. Admittedly, IVD studies may not have the same attraction because, in most cases, the subjects agree to provide a biospecimen for the study, but the information generated by donating a specimen is rarely shared with investigator/clinicians or subjects.

However, the safety and efficacy of IVDs is important. Laboratories and device manufacturers develop diagnostic assays to aid clinicians in diagnosis and management of health conditions and diseases. It requires various sample types—blood, urine, sputum, and swabs. The tests could claim to detect cancer cells, pathogens, analytes, and biomarkers of disease risk, and are used to monitor treatment or make ongoing clinical decisions.

When the rapid spread of COVID-19 led to a pandemic, IVD products became the rising star of clinical studies. In response to the national emergency, government agencies, laboratories, device manufacturers, and consumers took an interest in the availability of diagnostic testing to track disease prevalence and manage public health. With the current spotlight on IVD clinical trials, it is a good time to consider similarities and differences between medical devices and IVD medical devices and ways to demonstrate safety and effectiveness.

IVD Product Development and Regulatory Strategy

The U.S. Food and Drug Administration (FDA) regulates IVDs as medical devices subject to 21 CFR § 812 in the Code of Federal Regulations, the Investigational Device Exemption (IDE) regulation that sets the boundaries around how to introduce an investigational device into interstate commerce for the purposes of research. This IDE regulation identifies when an exemption is required from the FDA before distributing a medical device for a clinical study. In addition to FDA regulations, International Council for Harmonization (ICH) E6 Principals of Good Clinical Practice (GCP) are recognized by European countries, the U.S., and Japan as a standard for how to conduct human subjects research. This standard describes how best to protect patients and preserve the integrity of the data.{1} FDA also recognizes ISO 14155 from the International Organization for Standardization as applicable to clinical investigations of medical devices and ISO 20916, as it is specific to IVD clinical performance studies.

An IVD includes reagents, instruments, and systems used to collect, prepare, and examine specimens from the body intending to diagnose or aid in the diagnosis, screening, or monitoring of disease or physiological status.{2} IVD clinical performance studies need to demonstrate the safety and reliability of the test and the test results.

FDA classifies a medical device by risk, with a Class I device having the lowest risk and being exempt from the IDE regulation. These products must comply with all Good Manufacturing Practices (GMPs) (see 21 CFR 820) and a manufacturer can “register” the product and sell it without clinical performance evidence.

Class 2 devices are low to moderate risk, and they are “cleared” through the 510(k)/de novo pathway. Medical device 510k submissions identify a predicate device that is most similar to a proposed product’s intended use and technology characteristics to demonstrate “substantial equivalence” of the investigational product to the commercially available predicate device.

Class 3 devices are the highest risk devices, such as typical implantable medical devices or, in the case of an IVD, an HIV test that could cause significant harm to patients if the test result is inaccurate.{3} ICH E6 and the ISO standards are good guidance for conducting studies to gather appropriate device safety and performance data.

IVD Risks and Pivotal Study Design

ISO 20916 acknowledges study designs incorporating a reference measurement procedure that allows an assessment of “percent agreement” of the investigational test to the reference measurement that may or may not be the “predicate device.” When an assay claims to identify a specific target or analyte, a pivotal study of clinical performance may include testing a specimen on the investigational assay and comparing the results to testing on a comparator assay. The comparator may be an appropriate predicate technology, or may even be a different cleared or approved technology that measures the same target with even greater sensitivity.

When an assay claims to identify a biomarker that may aid in the diagnosis of cancer, the pivotal study for this product may require a comparison of the assay performance to a gold standard in cancer diagnosis—most likely a biopsy. In this case, the technology must also have a predicate device to pursue a 510(k) regulatory pathway, identify as a novel de novo product with a Class 2 risk, or follow a Class 3 premarket application (PMA) for FDA approval.

There are two risk indicators to consider in the clinical performance evaluation of IVD products. The first is the risk of a false or inaccurate test result to patients that would cause the FDA to consider the IVD as high risk. An example might be a companion diagnostic used to make a treatment decision (start or stop a therapeutic) or to monitor the effects of the therapeutic or adjust or titrate its dosing. This means there is a risk that if the assay result is incorrect, a patient may receive inadequate or toxic doses of the therapeutic or no therapeutic at all.

The second is the risk of the clinical performance study itself. Recall that institutional review boards (IRBs) overseeing safety and ethics at study sites serve as the FDA surrogate in device risk determinations. As noted earlier, non-significant risk (NSR) device studies do not require an IDE application; however, significant risk (SR) devices intended for research must have an IDE from the FDA before distribution.{4}

A device’s intended use and indications for use drive the risk classification of the device. If the risk of an incorrect test result is potentially harmful to subjects, the IRB/FDA may consider the device SR. For example, if a false negative test means a subject does not appropriately triage to a next step that prevents, treats, or mitigates disease or disease risk, the IRB/FDA may consider that high risk. Likewise, if a false positive test means a subject triages to a next step that is potentially invasive or high risk, the IRB/FDA may consider that high risk as well. The study may be NSR (noninvasive sample collection, clinical care at the clinician’s discretion, test results are not used to direct or manage patient care), but the intended use of the commercialized product may still be Class 3 risk requiring a full PMA submission to the FDA.

IRB members should know that IVD research is exempt from the IDE regulations if the device meets certain criteria, including a non-invasive sampling procedure and a test result that is not considered “diagnostic” without confirmation of the diagnosis by another medically established product or procedure. If the IRB deems the research study SR because inaccurate IVD results could lead to misdiagnosis and/or treatment error, an approved IDE is required to conduct the study.{4}

If there is an intent to disclose the investigational test result to the clinician and/or the subject, the protocol and informed consent should include an explanation of how a potentially false result will impact the subjects. The IRB will consider this risk to subjects in the determination of a NSR vs. SR study that would require an IDE. Sponsors may make an initial NSR determination based on the potential low risk of harm to the subject from participation in the study, including the risks associated with the use of the device. If the IRB disagrees and determines by a risk/benefit assessment that the research is SR, the sponsor must notify the FDA of the IRB determination within five working days and submit an IDE application before commencing the study. SR research reviewed by the IRB should include evidence of an IDE number from the FDA prior to approval to ensure agency awareness and appropriate regulatory oversight.

The IRB should be informed of, and especially consider, a risk/benefit determination for subject safety and welfare when any laboratory testing involves the analysis of human DNA, RNA, chromosomes, and proteins or metabolites that detect genotypes, mutations, or chromosomal changes and is therefore by definition genetic testing.{5} IRB submission information should include a description of the genetic testing and impact of potential results; a plan to manage significant genetic test results; an informed consent disclosure to subjects if the genetic testing could misidentify parentage or disclose a hereditary disease or genetic mutation associated with increased risk of disease; and details on the availability of subject and family genetic counseling and any plans to bank specimens for genetic testing.

ISO 20916 defines an “interventional study” as a study in which the investigational test result is disclosed to the clinician and/or the subject and used to manage the patient care during the study. Key regulatory points regarding disclosure of investigational IVD test results in an assay study include the following:

• The U.S. Department of Health and Human Services (HHS) and FDA regulations (45 CFR § 46 and 21 CFR §§ 50 and 56, respectively) are silent regarding the return of individual investigational laboratory test results to research subjects; however, using investigational test results to manage clinical care would seem to be increased risk if the test is not yet proven safe and effective.
• FDA may require IDEs for a broader set of clinical investigations, and it is unclear under such IDEs whether IVD research test results may be communicated to subjects.
• Clinical Laboratory Improvement Amendments (CLIA) regulations prohibit research labs from providing test results to patients generated by non-CLIA-certified labs when those results are provided for treatment purposes. Only CLIA-certified laboratories can release data to subjects and the data must be from validated tests.
• The Centers for Medicare and Medicaid Services (CMS) forbids any communication of test results to patients from non-CLIA-certified labs. Laboratories that perform testing for clinical research studies may not be CLIA-certified and often use unvalidated tests.
• The Health Insurance Portability and Accountability Act (HIPAA) requires patient access to results that are part of their designated record set (clinical researchers must release research data to study participants); however, the Office of Civil Rights within HHS has not provided guidance on how to interpret the term “designated record set” in the context of return of results from non-CLIA research labs.{6}

Some understanding of CLIA regulations helps put these points into perspective. Laboratories in the U.S. that perform testing on human specimens for diagnosis are regulated by CLIA. Three federal agencies—FDA (test risk categorization), CMS (clinical laboratory oversight), and the Centers for Disease Control and Prevention (scientific consultation)—support CLIA quality standards for laboratory testing to ensure accurate and reliable test results.

CLIA categorizes tests according to technical complexity and risks associated with false test results. The categories from lowest to highest are waived tests, moderate to high complexity, and high complexity tests. Prior to human specimen testing for clinical use, testing facilities must apply for a CLIA certificate corresponding to the category of testing the facility will perform.{7}

The reference to non-CLIA labs differentiates research labs that perform laboratory testing from clinical laboratories that perform testing on human specimens and report results to clinicians to use to manage clinical care. It makes sense then that agencies would prohibit disclosure of investigational test results to patients if those test results are generated by a non-CLIA-certified laboratory. It is, however, permissible to run an FDA pivotal clinical performance study in a non-CLIA-certified laboratory, so long as the assay development is compliant with GMP design controls and the test results will not be disclosed to subjects or clinicians for clinical care. 

Securing Biospecimens

The most obvious approach to acquiring specimens might be a prospective sample collection by obtaining informed consent from the target population and then collecting the specimen (e.g., swabs, stool, fluids, blood, etc.). In this case, the sample collection supplies are also accessory medical devices subject to risk assessment, device classification, and investigational use only (IUO) labeling.

FDA and ISO 20916 address the risks of sample collection and any potential harm associated with the sampling procedure as part of the device risk classification and the study risk determination by the IRB. ISO 20916 also considers the safety of the assay in the hands of the intended user while using it in the intended use environment on the intended use population as an element of risk assessment.

Typically, a study design mirrors the commercial testing scenario. For example, if an investigational test will be commercialized as an over the counter (OTC) product for lay users to purchase and test themselves, the study would enroll lay users who perform the test using only the quick reference guide (QRG) in a “simulated” home setting.

Depending on disease prevalence, there may not be enough of a target population (e.g., very small numbers of carriers of an infectious disease) to achieve the numbers of test results required to support the product claim. In this case, it may be an option to enrich a population for positives by using residual samples from known positives, buying banked samples from a broker ,and/or using spiked samples.

A study is not considered human subjects research so long as the specimens are transferred with no direct patient identifiers and there is no interaction with human subjects when samples are left over from routine care collections, acquired from banked sources who obtained the samples with the appropriate permissions, or obtained through some other contrived means.

Other related factors to be aware of on this topic include:

• In the U.S., such studies do not require IRB oversight or informed consent from subjects; however, it would be appropriate to request a central IRB exempt determination only for the purposes of due diligence and documentation.{8}
• In the U.S., an individual responsible for treatment, payment, or clinical operations is permitted to remove identifiers to create samples and annotated clinical data defined as a limited dataset under the HIPAA regulation.
• In this case, it is permissible to use a Material Transfer Agreement with Data Use terms (HIPAA transfer method) that permit transfer of the material and use and disclosure of a limited dataset without HIPAA authorization along with the transfer of the samples.
  • Alternatively, at the time of IRB request for an exempt determination, a waiver of HIPAA authorization request may be granted if:
    • Use and disclosure of HIPAA-defined Protected Health Information (PHI) involves no more than minimal risk to individuals and their privacy (there is an adequate plan to protect identifiers from improper use or disclosure, plan to destroy identifiers at the earliest opportunity, and adequate assurances the PHI will not be reused).
    • The research cannot be practicably completed with the waiver.
    • The research cannot be practicably completed without data—in this case, likely dates of service (i.e., date of sample collection, date of a testing result).
    • Privacy risks are reasonable in relation to the anticipated benefits.{9}
  • ISO 20916 permits the use of leftover samples for research without subject consent so long as there is no other interaction with the subjects and the test result is not being used to manage patient care.

Managing IVD Clinical Performance Studies

Site Qualification and Study Start Up

An IVD Clinical Performance Study may require a qualified laboratory for different kinds of testing. Some case examples follow:

• An investigational assay (a moderate- to high-complexity lab instrument) is deployed to a lab environment for trained laboratory operators to run a candidate test for results. This lab may be a qualified “research” lab, but so long as the study is not interventional and the test results will not be released to the clinician or subjects for clinical care, this lab is NOT required to have CLIA Certification. This lab however, must “qualify” to perform the testing according to the investigational assay’s instructions for use (IFU) and must be qualified for research activity (i.e., qualified test operators and GCP training). This lab is responsible for the investigational product, reagents, sample preparation, etc. and testing according to the study protocol. This makes this lab “engaged” in the research and requires that this lab be considered a “site” that the IRB must approve for participation. This laboratory “site” requires all standard essential documents required for activation. Key areas of query for laboratory qualifications should include:
  • Appropriate certifications for the assay type
  • Laboratory Director with principal investigator (PI) qualifications
  • Laboratory capability and qualifications to manage and track investigational product and specimens (traceability—parent/child sample chain of custody) and perform the specific testing (manual cytology, microscopy, pathology, etc.)
  • Ability to generate collection kits and labels correlating all specimens and aliquots or “child” samples to a single clinical subject*
  • Equipment and supplies required by the investigational assay IFU (freezers, refrigerators, centrifuge, laminar flow hood, reagents, antibodies, vortex mixer, cell sorter, 240-volt outlet, etc.)*
  • Laboratory information system conforms to 21 CFR § 11requirements for electronic signatures (individual accounts, log in credentials, auto log off, prompted password changes, limited log on attempts; at least two distinct components to eSignature, loss management for ID/passwords; user roles and permissions matrix, data quality checks, interface capability, internal testing; date and time stamp, virus protection, system controls to prevent external access)*
  • Audit trail and export capabilities that preserve data integrity and security
  • Written SOPs for clinical studies
• A clinical performance study may require “comparator” testing on an instrument already cleared or approved for testing or detection of the target analyte. Laboratories that perform commercially available testing to provide test results as comparator data in alignment with all of the following conditions are not engaged in human subjects research, because:
  • the services performed do not merit professional recognition or publication privileges;
  • the services performed are typically performed by those institutions for non-research purposes; and
  • the institution’s employees or agents do not administer any study intervention being tested or evaluated under the protocol.{10}

Further, an IRB requirement for oversight is limited to human subjects research and, in this case example, the lab is not engaged in human subjects research, because:

• the lab is performing services as a vendor;
• the services the lab performs are services typically performed for non-research purposes; and
• the lab is not interacting with subjects and is not receiving any personal data about subjects.

It is recommended that the study documents/trial master file (TMF) include an IRB exempt determination for this laboratory citing the salient factors (marked *) from above. When the IRB determines the reference lab is exempt from oversight, it also means lab personnel are not required to meet the experience and training obligations otherwise applicable to those who are engaged in research (i.e., GCP training). The TMF should include an executed vendor agreement between the lab and the sponsor, the appropriate CLIA certification (the laboratory is qualified to perform the services they typically provide for non-research purposes), and the IRB letter indicating the reference lab is exempt from IRB oversight.

• An investigational assay may be a point of care (POC), OTC, or direct to consumer (DTC) test that requires the clinical performance study to evaluate the test performance in the hands of the user in the intended use environment. For these kinds of investigational assays, be aware that:
  • a POC test intended use environment may require a CLIA Certificate of Waiver (for simple testing done for example in a doctor’s office)
  • an OTC or DTC test may require a simulated home use environment (not subject to CLIA regulations)

Investigational Product Accountability

In addition to traditional medical device accountability, ISO 20916 requires the same accountability tracking for all investigational reagents and accessories. These ancillary supplies are considered part of the investigational assay and should be labeled as Investigational Use Only (IUO).

Beyond device tracking, ISO 20916 requires accountability for specimens. These could be prospectively collected solely for research, might otherwise be banked/archived or contrived samples, or could be leftover clinical samples. Most sample tracking logs include variables critical to how the specimen performance is affected by any “excursions” from controls such as temperature, sample preparation, or specific technological processing steps to run the assay.

Some assays require special processing SOPs and/or require processing within conditions or a time window in which the samples are still considered “fresh.” Some samples are limited to a certain number of freeze/thaw cycles. Likewise, ISO 20916 addresses specimen chain of custody so that all of the specimen (which can turn into multiple child samples from the parent specimen) acquired from the subject or for the study is accounted for, including leftover samples when testing for the study is completed.

Data Management and Monitoring

Data collection for an IVD study is more about the relationship of multiple specimens to a single clinical subject compared to medical device data collection involving one subject, an index procedure or event, and then multiple longitudinal outcome measurements. A single IVD study subject may provide multiple specimens. These could include the same sample type but more than one sample, to allow for investigational assay testing as well as comparator assay testing. There might also be different sample types to allow performance evaluation of a test using, for example, a swab compared to urine.

An electronic data capture (EDC) configuration must connect a single subject and relative clinical data (demographics, disease history, symptoms, etc.) to potentially many samples (sample type, date/time of collection, storage, shipping, freeze/thaw, aliquot volumes, residual disposition, etc.) and test results (instrument, cartridge, reagents, quality control findings, date/time of testing, etc.). User comprehension, user experience, and observer surveys are common data collection events for assay testing for POC, OTC, and DTC use products and environments.

Managing data integrity often calls for a combination of data review and monitoring. Data review is the act of assessing data to identify blank fields, data outside boundary edits, missing data, and data trends. Data review is often facilitated by system-generated queries triggered by electronic edit checks built into the database.

Data review of instrument data, which is most often considered “original source,” is important to track samples, testing, and test results, which can be akin to tracking “enrollment” when the study does not include prospective specimen collection. Monitoring is the act of assessing data for verification to source documents. Data monitoring is performed by individuals qualified by appropriate training. Monitoring for IVD study data may be a combination of standard source data verification for clinical data, ensuring direct data capture on specimen and testing logs is complete, verification of accurate transcription into an EDC, and data review of instrument output.

Monitoring IVD studies includes all of the standard accountability for human subject protection, GCP, protocol training and compliance, maintaining adequate records and regulatory documents, and tracking site performance metrics. Specimen accountability has already been noted and should be addressed in the monitoring plan.

Adverse events (AEs) affecting the health and safety of subjects are uncommon in IVD studies, given most sampling procedures are not invasive and studies involving leftover or archived samples do not involve human subjects. AEs related to the use of an IVD medical device (adverse device effect) include “any AE resulting from insufficient or inadequate instructions for use…malfunction of the IVD (and) any event resulting from use error or intentional misuse of the IVD…. False negative or false positive results are not considered AEs unless seen in an interventional study where inappropriate patient management decisions are made based on those false results” (ISO 20916).

Conclusion

It is a simple and true statement that the U.S. FDA regulates IVDs as medical devices. IVDs are the same but different, a phrase and concept that recognizes both similarities and differences. The application of laws and regulations are the same for IVDs, but the lens for risk assessment, for example, is a different focus on accurate test results and how a false test result might cause harm to patients instead of bodily harm associated with implanted devices. Likewise, the same GCPs apply to medical devices and IVDs; however, with the latter, study implementation is “different enough” to have a separate ISO 20916 guideline.

There is a reported “bolus of companies in the diagnostics and genomics tools market” reporting hot products and business objectives at the 2023 JP Morgan Conference.{11} Words like liquid biopsy, cancer screening, cancer risk scores, multiplex respiratory panels, targets, biomarkers, and antigens highlight the investment in rising star diagnostics especially in oncology and infectious diseases. Large and small companies are keen to move new IVD products to market and will tap into CROs and clinical sites to support the clinical validations required for regulatory submissions.

With this limited review, perhaps there is new awareness of compliance obligations and operational logistics associated with IVD clinical performance studies. It might be time to explore talent, update SOPs, or edit templates and tools to add attention to the unique aspects of IVD products, study designs, and tactical implementation of IVD clinical trials.

References

1. FDA. 2018. Guidance for Industry: E6(R2) Good Clinical Practice: Integrated Addendum to ICH E6(R1)
2. 21 CFR § 809.3 and ISO 20916
3. FDA. 2020. Classify Your Medical Device
4. FDA. 2006. Information Sheet Guidance for IRBs, Clinical Investigators, and Sponsors: Significant Risk and Nonsignificant Risk Medical Device Studies
5. The Genetic Information Nondiscrimination Act of 2008—U.S. Equal Employment Opportunity Commission
6. Secretary’s Advisory Committee on Human Research Protections (SACHRP) Recommendations. 2016. Sharing Study Data and Results: Attachment B: Return of Individual Research Results
7. Bradshaw N, Rice L. 2020. NAMSA. Clinical Trial Plan: CLIA-Waived Point-of-Care Test
8. 45 CFR § 46.101b
9. Office of Civil Rights. 2003. HIPAA Privacy for Research (codified in 45 CFR § 164 certain sections). research.pdf (hhs.gov)
10. Office for Human Research Protections Guidance. 2009. Determining When Institutions are Engaged in Research
11. 360Dx Business News “staff reporter” JP Morgan Healthcare Conference, Day 1 Update. January 10, 2023.

Wendy Schroeder, BSN, CRCP, CCRC, ACRP-PM, (wschroeder@namsa.com) is Principal Strategy Consultant, Clinical, for NAMSA and Consultant at Schroeder Clinical Research Consulting, LLC in Phoenix, Ariz.