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Sponsors are advised to carefully consider the risks associated with using a CDx
in any clinical study and the potential impact of CDx results on decisions to treat
patients with investigational GTx products. It is particularly important to enter
phase 2 clinical trials with a proposed clinical cutoff based on results from prior
analytical and clinical studies. Then, based on how the proposed clinical cutoff
performs in phase 2 studies, the cutoff may then be validated in phase 3 for registrational studies. If the cutoff used in the phase 2 study is set too conservatively, it
may be difficult to demonstrate nonsignificant risk and defend use of a higher
cutoff in the phase 3 studies to support registration. While not impossible to demonstrate, a change in the cutoff could require supportive evidence to minimize the
risk to subjects, such as a small trial prior to the larger registrational trial.
Therefore, the data to support an appropriate clinical cutoff in phase 2 should be
carefully considered.
16.2 Development of CTAs for Use in GTx
Clinical Trials
There are several factors to consider for a CTA (i.e. a potential CDx) that will be
used in a GTx clinical trial. The CTA’s development timing and corresponding
quality system requirements must be considered with the long‐term view for
whether the CTA will become a CDx for market entry and commercialization.
Further, how the CTA is used to make decisions for subjects enrolled in the GTx
clinical trial as well as the GTx trial phase are important considerations for the
CTA’s validation strategy.
For example, the GTx being used in first‐in‐human trials where an analytical
cutoff for the CTA is based on neutralizing antibody (NAb) titers at the limit of
detection, but a clinical cutoff for commercial application is not yet known? In
this example, assay validation requirements may be limited to analytical sensitivity and precision based on how the CTA may initially be used in the GTx clinical trial.
Another example could be when GTx are being used in a rare diseases but pivotal clinical trials, where the clinical cutoff may be determined through previous
studies, and the CTA is being used to enroll subjects. In this example, analytical
validation of the assay would need to be more robust, and other factors described
below must be evaluated.
16.2.1 Stratification vs. Selection
An important consideration for any clinical trial where a CTA is to be used, and
for which a CDx may eventually be made available to the market, is whether the
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assay is used for stratification vs. selection. Stratification means that the CTA is
used to assign subjects to different arms of the GTx clinical trial, but results from
the CTA itself are not used to determine the treatment that the subject receives[8].
In contrast, selection means that results from the CTA itself are used to determine the treatment of the subject receives during the GTx clinical trial and is often
part of the inclusion/exclusion criteria for subject eligibility.
Understanding how the CTA/CDx will be used in the GTx trial (stratification vs.
selection) can influence not only the eventual regulatory pathway for market
entry of the CDx, but also the risk determination (and therefore assay validation
requirements) for use of the CTA in the GTx trial.
16.2.2 Regulatory Risk Determination: Significant
or Nonsignificant?
Determining the risk associated with CTA use in a GTx clinical trial is a critical
step for preparing Institutional Review Boards (IRBs) and potentially the FDA to
review a clinical trial protocol with an associated CTA. In the section above, one
critical assessment is whether the CTA will be used to either stratify or select subjects in a clinical trial to receive the investigational GTx.
To understand and make a risk determination, it is important to first understand how the FDA views risks associated with medical devices (including IVDs
as CTAs)[10]. The FDA classifies medical device studies into three types: significant risk (SR), nonsignificant risk (NSR), and exempt, all in accordance with the
21 CFR 812 regulation.
A significant risk device under 21 CFR 812.3(m) means an investigational
device or CTA that:
1) Is intended as an implant and presents a potential for serious risk to the health,
safety, or welfare of a subject;
2) Is purported or represented to be for use supporting or sustaining human life
and presents a potential for serious risk to the health, safety, or welfare of a
subject;
3) Is for a use of substantial importance in diagnosing, curing, mitigating, or
treating disease, or otherwise preventing impairment of human health and
presents a potential for serious risk to the health, safety, or welfare of a
subject; or
4) Otherwise presents a potential for serious risk to the health, safety, or welfare
of a subject.
Definitions 3 and 4 are the most relevant to CTAs used in investigational GTx
trials. The concern about CTA use is that incorrect test results can present a
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significant risk when they lead to mismanagement of a subject’s care. In the context of GTx, an incorrect result could mean either that an eligible subject would
not receive the investigational GTx or that an otherwise ineligible subject receives
the investigational GTx. Incorrect results could also lead to incorrect selection/
non‐selection of subjects into the GTx clinical trial, which might impact the data
supporting the safety and efficacy of the CTA and GTx. In most instances, the
risks associated with the GTx will outweigh the risks of incorrect CTA results.
Still, it is important that this risk is minimized through proper validation that is
documented in a risk/benefit determination document.
When the CTA is intended to stratify subjects into different arms of a GTx study,
results from the CTA itself are not being used to determine treatment of the subject. Therefore, such studies are normally determined to be NSR, and while IRB
approval is still required, FDA approval of a CTA as an NSR would likely not be
required. In contrast, when the CTA is intended for used to select subjects eligible
to receive the investigational GTx, inaccurate results could put subjects at potential risk. Therefore, the CTA is generally considered an SR device subject to both
IRB and FDA approval for use in the trial through submission of an IDE application. Supportive evidence for an IDE application will include sufficient data demonstrating that the CTA provides accurate results and answers to the following
questions[11], included in the application:
1) Will use of the results from an investigational IVD (e.g. a CTA) lead to some
study subjects foregoing or delaying treatment that is known to be effective?
2) Will use of the results from an investigational IVD expose study subjects to
safety risks (e.g. adverse events from the investigational therapeutic product)
that exceed the risks encountered with the control arm therapy or standard
of care?
3) Is it likely, based on existing knowledge about the relationship between the
biomarker and the investigational therapeutic product, that incorrect results
from the investigational IVD would present a potential for serious risk to study
subjects?
4) Does use of the investigational IVD require invasive sampling that is not part
of the standard of care?
A nonsignificant risk device study under the IDE regulation 21 CFR 812 is one
that does not meet the above definition of an SR device study and is subject to the
abbreviated IDE requirements under §812.2 (b). These include labeling per the
IDE regulation ((§812.5) and must bear the statement “CAUTION– Investigational
Device. Limited by Federal (or United States) law to investigational use.”; IRB
Approval; Informed Consent per 21 CFR 50; monitoring to protect the human
subjects and assure compliance with approved protocols; maintaining specific
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records and reports as required by the IDE regulations (§812.2(b)(1)(v)) and prohibitions related to the promotion, marketing, and misrepresentation of the investigational device (§812.7).
An exempt study may be a study evaluating consumer preference testing or use
of an already FDA‐cleared device in a study as long as there is no collection of
safety or effectiveness data[12].
When it may be unclear whether the CTA is SR or NSR, study sponsors may
request a study risk determination under the FDA’s Q‐Submission Program[2].
Study sponsors can then submit supportive documentation to the FDA to determine whether use of their CTA in the GTx trial results in an SR or NSR study.
Under the current guidance document, the FDA has 90days to respond to the
sponsor with a determination. One benefit of this approach is that if the study
sponsor receives an NSR designation from the FDA, this documentation can be
used when submitting study protocols to IRBs for review and approval. This can
prevent delays from IRBs if they see the FDA has deemed the study NSR.
16.2.3 CTA Design Considerations
When considering the design of a CTA for use in an investigational GTx clinical
trial, there are factors to consider beyond the science to support use of the CTA. For
example, if the CTA will become a CDx, the design of the CTA should be modeled
in accordance with 21 CFR 820, and elements of design control requirements
should be in place. Depending on where the CTA is in the development cycle,
documentation must support the requirements set forth by the CTA and include
the various development, verification, and validation requirements for the CTA to
be submitted to FDA as a CDx.
Further, if the CTA will become a CDx, the design of the CTA to be used in the
investigational GTx clinical trial should be under a “design freeze.” This generally
means the following:
● The critical reagents and suppliers have been identified;
● The test method and data analysis specifications have been developed and doc-
umented; and
● The key equipment used to execute the test method has been identified,
installed, and qualified for use during the clinical trial regardless of phase.
For any studies in which the investigational GTx and CTA have been or will be
used, it is also critical that subjects are consented for use of leftover samples in
various ongoing research and that results from testing subject samples using the
CTA can be used in a regulatory submission. This added consent can often be
overlooked by sponsors. The availability of leftover samples from the clinical trial
allows for any bridging studies to be conducted between the CTA and final CDx,
should changes to the design be necessary. However, at the time that the CTA is
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being used in a registrational GTx clinical trial, sponsors should strive to be using
a CTA that will not undergo a design change prior to submission as a CDx.
16.2.4 CTA Validation Requirements
Currently, there are no established rules or guidance on how much testing is
required for a CTA to be used in an investigational GTx clinical trial. To use an
assay as a CTA, the IVD manufacturer will need to validate the assay per the CLIA
program regulations (42 CFR 493.1253). Data derived from the CLIA validation
should be used to support the IDE application, including evaluating accuracy, precision, analytical sensitivity and specificity, reportable range, reference interval,
and any additional performance metric to ensure accurate test performance. Even
with these data, CTA validation must still meet rigorous standards for safe and
effective use of the CTA to stratify or selection patients into the investigational
GTx clinical trial; however, the FDA may require fewer studies with smaller sample sizes and replicates. A key consideration in determining the level of validation
required for the CTA will depend on how the CTA is used in the investigational
GTx clinical trial and the risks associated with erroneous results as assessed above
in Section 16.2.2. Additionally, the same Q‐submission process described in
Section16.2.2 can be leveraged for submission of a “pre‐IDE” meeting with the
FDA to outline how the CTA will be validated for use in the investigational GTx
clinical trial.
16.3 Best Practices forSample Banking and Consent
ofSubjects
From a strategy perspective, it is strongly recommended to bank clinical samples
from all subjects tested not only in the pivotal trial but also across all phases of the
GTx clinical trials, including patients excluded in the trials. The samples are likely
from a rare patient population and not easily accessible from standard biobanks.
However, in order to do so, GTx sponsors must include the proper informed consent that will allow testing of the patient samples for enrollment in the current
trial as well as downstream testing for analytical validation of the final CDx or for
a bridging study where testing of all pivotal study samples (positive and negative
or above and below the clinical cutoff) will need to be conducted with the
final CDx.
16.3.1 Validation Strategies for CDxs for Commercial Use
As described above for the CTA, there are several factors to consider when validating a CDx for commercial use. The CDx’s development timing and the impact of
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any design changes between the CTA and CDx must be assessed. For example, if
there are differences between the CTA and CDx that raise the level of a design
change, all prior analytical and clinical data generated on the CTA must be
assessed for impact on the CDx. This impact assessment includes review of the
data generated with the CTA against the design changes to the CDx to determine
whether additional studies are required.
Other factors to consider are whether the CDx and CTA are manufactured by
the same company vs. undergoing a design transfer and manufacturing scale‐up
that would require additional validation studies to be performed.
16.4 Design Considerations
The design of a CDx should be considered early on in its development program.
As discussed above, limiting the differences between the CTA and CDx will make
it easier for sponsors to validate the CDx for commercial use. As stated in
Section16.2.3 for the CTA, the CDx must also conform to the requirements stated
in 21 CFR 820, and elements of design control requirements must be in place. If
the designs of the CDx and CTA are the same, then the design control documentation used during the development of the CTA may be leveraged for the CDx.
However, if the CDx is significantly different from the CTA, the design control
documentation to support the CDx must comprehensively address the design of
the CDx from feasibility through validation. In this case, the CTA may provide
supportive information for documenting feasibility of the CDx.
16.4.1 Single-site vs. Distributable Kit
The typical product configuration for a CDx is an IVD kit that can be sold to and
run in any CLIA laboratory in the United States and potentially abroad. However,
GTx CDx that evaluate NAbs for each patient requires working cell banks to run
the assays. This component of CDx does not align well with a distributable kit
model due to potential variability from cell bank to cell bank. Therefore, we recommend a single‐site testing model for commercialization in which all components and quality system requirements for performing these assays are tested at a
single laboratory in a controlled environment. Therefore, the sponsor would submit a PMA for the assay run out of a single site for use as the GTx CDx.
16.4.2 Validation Requirements
To submit a CDx for approval by the FDA, the CDx must be validated in accordance with specific standards and best practices known to be acceptable by the
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FDA in the absence of a published standard. The CLSI publishes specific standards for how diagnostic tests should be validated and which typically specify the
number of samples, lots, replicates, etc. to be tested and methods for analysis of
test results. It is the obligation of the sponsor to set acceptance criteria for validation studies and document the requirements of the validation as part of the analytical validation study protocol and report.
Table16.2 below provides the general list of required studies that must be performed to support validation of a CDx for submission to the FDA. Depending on
whether the CDx is qualitative, semi‐quantitative, or quantitative, some studies may
Table16.2 Typical studies required forvalidation and FDA submission ofa CDx.
CLSI
Study
guideline CLSI standard name
Reference Range
Study
Analytical
Sensitivity
(LoB/D/Q)
Accuracy EP12‐A2 User Protocol for Evaluation of Qualitative Test
Precision EP05‐A3
Endogenous &
Exogenous
Interferences
Cross Reactivity EP07‐A3
Carryover/
Cross
Contamination
EP28‐Ac3 Defining, Establishing, and Verifying Reference
EP17‐A2 Evaluation of Detection Capability for Clinical
EP12.A2
EP07‐A3
EP37Ed1E
N/A Evaluation of carry‐over and cross‐contamination
Intervals in the Clinical Laboratory; Approved
Guideline— Third Edition.
Laboratory Measurement Procedures; Approved
Guideline—
Performance.
Evaluation of Precision of Quantitative Measurement
Procedures; Approved Guideline—
User Protocol for Evaluation of Qualitative Test
Performance.
Interference Testing in Clinical Chemistry, 3
Supplemental Tables for Interference Testing in
Clinical Chemistry, 1
Interference Testing in Clinical Chemistry, 3rd Edition.
Supplemental Tables for Interference Testing in
Clinical Chemistry, 1st Edition
between wells and its effect on assay results.
Specifically, the study should evaluate the potential
for carry‐over between wells with high levels of nAbs
to wells with low nAbs by alternating high‐ and
low‐level samples in a checkerboard pattern or
columns in a plate.
Second Edition.
st
Edition.
Third Edition.
rd
(Continued)
Edition.
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Table16.2 (Continued)
CLSI
Study
guideline CLSI standard name
Sample
Stability
Reagent Shelf‐Life
Stability
Reagent Open
Vial Stability
Tube Type
Equivalency Study
Linearity EP06Ed2 Evaluation of Linearity of Quantitative Measurement
High‐Dose Hook
Effect
N/A Evaluation of all possible sample storage conditions,
including long‐term frozen stability, short‐term
stability (room temperature and/or refrigerated),
freeze/thaw cycles, and transport stability.
EP25‐A Evaluation of Stability of In Vitro Diagnostic
Reagents.
EP25‐A Evaluation of Stability of In Vitro Diagnostic
Reagents.
EP14‐A2 Evaluation of Matrix Effects.
Procedures.
N/A Determine if the assay is susceptible to a high‐dose
hook effect and at what concentrations of AAV
inhibitory antibodies the high‐dose hook effect occurs.
or may not apply. But as a general rule, for a CDx with a specific clinical cutoff for
which results may be expressed as “positive/negative” or >/≤ a given level, the FDA
expects that samples used in validation studies are within ± 20% of the clinical cutoff. The cutoff must be determined prior to conducting these studies, which is
informed by the GTx partner based on GTx clinical trials prior to the pivotal study.
And for a CDx for which there is no specific clinical cutoff but for which results will
be reported in a quantitative manner, the FDA expects that samples used in validation studies include multiple samples across the measuring range of the CDx.
A strategy for CDx validation considers that there are no anticipated changes
between the CTA and CDx. In this case, during the CTA validation phase, sponsors may want to conduct some of the studies listed below to leverage results from
the CTA validation toward submission of the CDx, saving time and effort at the
end of the development cycle.
16.5 Bridging Studies
A bridging study is only required when the final, locked CDx was not utilized for
patient inclusion/exclusion in the pivotal clinical study with the GTx. A bridging
study evaluates efficacy of the therapeutic product in subjects selected by the CDx
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by assessing both concordance and discordance between the final CDx and the
CTA used in the pivotal clinical study while using the same specimens from subjects who were tested for the investigational GTx in the pivotal clinical study.
Statistical analysis of performance for the final CDx needs to consider any potential impact of missing samples not available for the bridging study. The ability of
the CDx to predict the efficacy of the therapeutic product can be supported indirectly by high analytical concordance with the CTA on a large number of representative samples, including samples from subjects excluded from the
investigational GTx clinical trial because they were below or above the threshold
established by the CTA. Thus, the FDA’s assessment of the clinical validity of the
CDx relies on extrapolating the clinical performance characteristics of the CTA to
the clinical performance characteristics of the CDx[8].
Bridging studies can prove challenging if the sponsor has not retained samples
from the investigational GTx clinical trial, including samples from patients who
were in and excluded from the trial, or if retained samples have not been demonstrated to have long‐term sample stability under the specified storage conditions.
This is a critical point in that lack of sample stability data will preclude use of
those samples in the downstream bridging study, which is important for GTx for
rare diseases where there may be a limited number of patients who even qualify
for clinical study enrollment.
As discussed above, the ideal scenario for the sponsor is when the CTA used in
the investigational GTx registrational or pivotal clinical trial is the same as the
eventual CDx to be submitted to the FDA and for commercial launch. However, it
is not always possible for the CTA to be the same as the CDx. In this event, the
performance criteria in the bridging study will need to consider any differences
between the CTA and CDx without undermining the ability of the study to demonstrate clinical validity of the CDx and show that results obtained with the CTA
are equivalent to results obtained with the CDx.
The ideal bridging study is one in which all samples tested with the CTA are
retested with the CDx, valid test results are obtained, and those results are used to
assess comparative performance conducted under an approved protocol with prespecified statistical analyses. If only a subset of samples is available for retesting,
the sponsor should ensure that the characteristics of the subset adequately reflect
the characteristics that affect test performance and that the characteristics of the
subjects that may affect therapeutic product efficacy (e.g. patient demographics
stage of disease, stratification factors) are proportionally preserved in the retest
sample set when compared to the samples in the original set. For the bridging
study, the CDx must test both positive and negative samples or samples from
patients that were included and excluded from the pivotal trial for the bridging study.
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16.6 Commensurate Regulatory Review and
Approval of GTx CDx
It is the goal of the GTx and CDx sponsors, along with the regulatory authorities,
to have commensurate approval of the CDx PMA with the GTx Biologics License
Application (BLA). This requires close collaboration between the GTx and CDx
sponsors early in the development of the GTx to ensure that an appropriate CTA
to CDx product development plan and strategy can be developed and executed,
including the regulatory submissions to the FDA for both the GTx and CDx. For
the CDx, the pre‐submission process will be critical to gain valuable guidance and
input from the FDA prior to conducing the assay validation studies per CLSI
guidelines and preparing the FDA for the upcoming modular PMA submission.
Timing and coordination across both FDAs Centers for Biologics Evaluation &
Research (CBER) and Centers for Device & Radiological Health (CDRH) is critical
to ensure contemporaneous approval.
However, it is within the FDA’s discretion to determine whether the GTx and
CDx must be approved at the same time. Because GTx sponsors may come late to
the CDx sponsor, the CDx sponsor may be unable to complete the required design
control documentation and analytical validation per the CLSI guidelines to support parallel submissions to FDA. Therefore, frequent communications with the
FDA on study progress and submission timing are essential for helping ensure
potential GTx approval with the promise of a CDx.
16.7 Concluding Sections
16.7.1 Summary of Validation Considerations for CTAs/CDx in GTx
Clinical Trials
The early steps of development of a CTA for a GTx are critical in ensuring long‐
term success in commercialization through contemporaneous approval with the
GTx or as a post‐market commitment for the GTx. The GTx and CDx sponsors
need to determine the type of assay as well as how the assay will be used in the
final patient journey for treatment in clinical trials. This will inform the risk determination and positioning with the FDA’s IDE requirements. The assay should be
analytically validated to CLIA as early as possible to ensure the assay is accurate
and reproducible. Further, the quality system should be put into place prior to
CLIA validation and continued throughout the product development as this is
critical for design control. All patients from first‐in‐human through pivotal studies should be consented such that the samples are consented to and available for
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