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15.4 Development Process 387
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AAV Capsid Proteins) have demonstrated both age‐related increases in total and
neutralizing antibody titers against various AAV capsids. Extensive preclinical
data, as well as emerging clinical experience, illustrate that higher preexisting
antibody levels in the blood may be able to neutralize a significant proportion of a
given AAV dose. AAV clinical experience to date has established that these products are well tolerated and harbor acceptable safety margins, yet health authorities and industry are engaged in ongoing discussions/negotiations to maintain an
acceptable benefit‐risk scenario for intended target populations and therefore
may require a CDx. Further recommendations regarding the need for a CDx for
the development and use of a GTx product are outlined in an FDA guidance[10].
However, within the AAV GTx space, CDx remain in their infancy with only two
CDx approved; one in Japan and the other in US and EU.
15.3 Overall Strategy
The preferred, and more expedient, approach is co‐development of the CDx and
the therapeutic drug product. This was the approach used for HercepTest™, the
CDx developed alongside trastuzumab for the treatment of breast cancer. Through
early collaborations, the performance of the device can be assessed both analytically and clinically to ensure that eligible patients will receive the appropriate
therapy[11]. One of the ways that this can be achieved is through use of the analytically validated version of the assay in clinical trials testing to screen patients
for enrollment into the trial, which facilitates early assessment of device safety
and efficacy as it pertains to the therapeutic. Additionally, co‐development can
lead to contemporaneous approval of the CDx so that the diagnostic can be made
available for use when the drug therapy is approved.
However, there may be cases where it is not possible to conduct contemporaneous development of both the invitro diagnostic and the drug due to the novelty of
the test analyte, emerging safety or efficacy issues in development of the therapeutic or in the case where an existing device has already been developed by a
manufacturer. In these instances, approval of the therapy may be delayed until
marketing authorization of the CDx is received.
15.4 Development Process
There are several gating stages that define the development pathway of an invitro
diagnostic that is validated for use in clinical trials for the drug product and ultimately submitted for regulatory approval as a CDx as illustrated in Figure15.1.
Throughout each of the phases of device development, the project team, generally
15 Introduction toCompanion Diagnostics forGene Therapy
Ensure device meets
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388
Dene device design
Figure15.1 Process diagram for development of a companion diagnostic.
comprised of members from the IVD manufacturer and drug developer, should
meet to discuss program requirements and results.
ered to be Class III medical devices, and as such, must be developed under the
regulatory requirements of 21 CFR 820[12] in the United States. In the European
Union (EU), CDx are categorized as Class C and must be developed to comply
with the IVDR. Compliance with 21 CFR and IVDR requires organizations to
maintain an effective Quality Management System (QMS) that addresses applicable regulatory requirements. Conformance to ISO 13485[13] is often used to help
comply with these regulatory requirements. ISO 13485 is a voluntary global standard that is an approach accepted by regulators to assure that a company is meeting
QMS expectations for medical devices. Although both 21 CFR 820 and ISO
13485[13] pertain to the Quality Management System (QMS for medical device
manufacturing, there are some differences between these regulations. However,
in 2022, the US FDA recently published a proposed rule to harmonize 21 CFR 820
to the ISO 13485 QMS standard[14].
uisite is the accreditation of the laboratory that is developing, validating, and performing the CDx. In the United States, laboratories should hold accreditation
through the College of American Pathologists (CAP) or the Clinical Laboratory
Improvement Amendments (CLIA), which is regulated through the Centers for
Medicare and Medicaid Services (CMS). These organizations ensure that laboratories meet quality standards for medical testing, which is performed under the
supervision of a medical director.
Initial assessment of
device performance
requirements
intended use
Feasibility
Development
Validation
Risk
determination
IRB/Regulatory Agency
IUO device
Validation
Clinical
investigations
Additional design
requirements/Device
changes?
YES NO
Regulatory
submission
It is important to note that IVDs intended for use as a CDx are generally consid-
In addition to the aforementioned QMS regulations, another important prereq-
15.4 Development Process 389
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During CDx development, it is common to perform feasibility studies designed to
assess analytical performance and identify potential concerns at an early stage.
Additionally, these studies can guide the development team toward design requirements that are required to meet the needs of both the device and the therapeutic.
After initial feasibility, a more formal design development process can begin.
This stage includes detailed planning and documentation of the outputs from the
device design requirements. Where possible, studies intended to support device
requirements should be designed using published standards such as those from
the Clinical and Laboratory Standards Institute (CLSI) or direct guidance received
from a regulatory agency. Procedures for the use of the device in the clinical setting and the manufacturing process should also be optimized during this stage of
development.
Once the design phase is complete, transfer of the device into production can
occur. Production of the device generally follows two configurations: (1) a single‐
site model, where commercial testing would be performed at one location, or
(2) a distributed kit format, where the test is able to be performed at any qualified
laboratory. It is at this point that numerous validation activities are performed to
ensure that the device meets its intended use and, subsequently, is ready for use in
the clinical setting. Validation studies should encompass all inputs from the
device design requirements and may include software, analytical specifications,
and process validations. Device validation should be rigorous and can take several
months to complete depending upon the design requirements. For additional
detail on the analytical, as well as clinical, validation of CDx, please refer to
Chapter16.
At the conclusion of validation, the device is designated as “Investigational Use
Only” (IUO) and can be considered validated for use in clinical studies of the
targeted therapy. However, use of the IUO device in clinical studies is predicated
by assessment of risk to the patient. Risk determination for the device is captured
through several pathways. As the process followed for the drug, an Institutional
Review Board (IRB), academic or commercial, is required to weigh benefit and
risk prior to use of the IVD in clinical testing. An additional consideration of risk
can be achieved through submission of an application to the regulatory agency
requesting their assessment of risk for use of the device in a clinical investigation.
In the United States, a Significant Risk Determination (SRD) can be made through
a submission to the FDA[15]. In this submission, the device manufacturer will
provide the agency with information about the clinical study design as well as the
device and its intended use. Should the FDA conclude that a device poses a
Significant Risk (SR), an Investigational Device Exemption (IDE) is required prior
to initiation of the clinical study. The IDE application contains additional detail
and data supporting the development and validation of the device for its intended
use and must demonstrate device compliance with IDE regulations (21 CFR 812).
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390
Risk assessment is also recognized for clinical trials using a medical device in the
EU, and a Performance Evaluation Application (PEA) must be submitted to competent authorities at the country level prior to use of the device in the clinical study.
During clinical investigations, the IUO device is used to screen patients for
enrollment into the study and is the point at which data will be generated for the
performance, efficacy, and safety of the device. At this stage, it may become evident that additional device requirements or modifications are needed from either
the analytical or manufacturing perspective. All changes are subject to additional
verification and validation studies and, if significant, will require notification to
regulatory agencies if the device is being used under an IDE or PEA.
Near the conclusion of clinical investigations, the collected data, especially that
from pivotal studies, will be subjected to rigorous statistical analysis as a function
of several categorical variables (e.g. demographics, prophylactic treatments) and
continuous variables (e.g. age, diagnostic test results). This assessment of clinical
data, along with a summary of safety and efficacy of the drug, will be provided to
regulatory agencies in a marketing application.
After completion of device development, the project team will prepare a marketing application for submission to regulatory agencies for approval of the device
as a companion diagnostic. Although not a strict requirement, the preference is
for concurrent submission for both the drug and device, therefore project teams
from both the device and drug sides often work closely to ensure accurate information is captured in both applications.
Device marketing applications (e.g. PMA, 510(k), and the Humanitarian Device
Exemption (HDE) (US), Technical File (EU)) are a complete summary of activities performed to ensure that a device meets the requirements of its intended use
in a safe and effective manner. These submissions will include a technical section
for non‐clinical studies, such as those performed during device validations.
Clinical investigations are also presented and include study protocols, safety and
effectiveness data, and adverse events for both the device and the drug. Additional
information about the QMS, software, and device labeling will also be included.
After submission, regulatory agencies will review all materials and provide
feedback or make additional requests for information. The duration of this process can vary depending on the complexity of the device and can be tied to drug
approval timelines.
15.5 Considerations forCommercialization
Early planning for the post‐market setting helps ensure smooth commercial
launch of the CDx and drug therapy. Once again, this process requires dedicated
References 391
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collaboration between device and therapy manufacturers and discussion should
begin prior to submission of a marketing application.
One of the first, and perhaps most important, considerations for a successful
commercialization strategy is logistics. The workflow of specimen collection,
transport, testing, and results may seem straightforward, but can also meet unforeseen obstacles. Teams may find it useful to engage healthcare systems prior to
launch to request feedback about their processes and determine the need for education and support programs. Furthermore, any marketing collateral used in support
of the CDx and therapeutic should be co‐developed to ensure consistency in the
information provided to healthcare providers and patients.
Depending upon the testing location for the CDx, additional complications may
arise with global programs, which may require more nuanced strategies. Teams
may encounter country‐specific import and export requirements that may require
additional support and can add to shipment transit times. Data privacy regulations and reimbursement requirements can also differ depending on the location
of the patient.
15.6 Conclusion
The requirement for a CDx may be imposed by regulatory bodies for the marketing approval of a GTx product. The development of a CDx can be complex and
typically involves extensive interactions between the diagnostic company, the
drug developer, and regulatory bodies to fashion a successful approach. The
following chapters go into additional detail about the validation of CDx products
(see Chapter16) and regulatory considerations for CDx (see Chapter17).
References
1 US Food and Drug Administration, 2018. Companion Diagnostics. https://www
.fda.gov/medical17 April 2023).
2 HERCEPTIN (trastuzumab) (1998). http://www.accessdata.fda.gov/drugsatfda_
docs/label/2010/103792s5250lbl.pdf (accessed 17 April 2023).
3 US Food and Drug Administration (2014). In vitro companion diagnostic devices,
guidance for industry and food and drug administration staff.
4 Regulation (EU) (2017). 2017/746 of the European Parliament and of the
Council, Official Journal of the European Union, 60.
5 Japan Pharmaceuticals and Medical Devices Agency (2013). Notification on
approval application for invitro companion diagnostics and corresponding
therapeutic products.
devices/in- vitro- diagnostics/companion- diagnostics (accessed
15 Introduction toCompanion Diagnostics forGene Therapy
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392
6 Scheerens, H., Malong, A., Bassett, K. etal. (2017). Current status of companion
launch. Clin. Transl. Sci. 10 (2): 84–92.
7 US Food and Drug Administration (2022). List of cleared or approved companion
diagnostic devices (invitro and imaging tools), https://www.fda.gov/medicaldevices/in- vitro- diagnostics/list- cleared- or- approved- companion- diagnosticdevices- in- vitro- and- imaging- tools (accessed 17 April 2023).
8 Sayed, N., Allawadhi, P., Khurana, A. etal. (2022). Gene therapy: comprehensive
overview and therapeutic applications. Life Sci. 294.
9 Wang, D., Tai, P.W.L., and Gao, G. (2019). Adeno‐associated virus vector as a
platform for gene therapy delivery. Nat. Rev. Drug Discovery 18: 358–378.
10 US Food and Drug Administration (2020). Human gene therapy for rare disease.
11 US Food and Drug Administration (2016). Principles for codevelopment of an
invitro companion diagnostic device with a therapeutic product.
12 US Food and Drug Administration (2022). Code of Federal Regulations Title 21,
Subchapter H, Medical Devices.
13 International Standards Organization (2016). ISO 13485:2016, Medical devices–
quality management systems– requirements for regulatory purposes.
14 US Federal Register, Vol. 87, No. 36, February 23, 2022, Proposed Rules, Medical
Devices; Quality System Regulation Amendments.
15 US Food and Drug Administration (2006). Information sheet guidance for IRBs,
clinical investigators, and sponsors, significant risk and nonsignificant risk
medical device studies.
16
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Validation forGene Therapy Companion Diagnostics
Karen L. Richards and Kennon Daniels
Precision for Medicine, Bethesda Metro Center, Bethesda, MD, USA
16.1 Introduction
Gene therapy has sparked great interest among researchers, healthcare providers,
and patients alike because it offers the possibility of new cures, particularly for
rare diseases with a genetic basis. However, the field is in its nascent stages, and
the ideal methods and solutions for unlocking the full potential of gene therapies
(GTx) are still being developed. In recent years, the requirement for development
of tests to detect antibodies against the vectors used to deliver the human vector‐
based GTx product to patients to appropriately select patients for eligibility to
receive the GTx and to support market authorization of the GTx has been introduced by Food and Drug Administration (FDA). This includes a requirement to
make such tests available as a companion diagnostic (CDx) requiring market
authorization at the same time as the GTx approval. In this chapter, we explore
general principles for validating a CDx to optimize the likelihood of preclinical
and clinical trial development success. We describe regulatory guidelines and
explain how CDx sponsors can ensure a scientifically valid diagnostic development plan to support contemporaneous premarket approval (PMA) by FDA.
393
16.1.1 Overview of FDA Oversight for the Use of Assays in Gene
Therapy Clinical Trials and the Path to Commercialization with
Corresponding Level of Validation
Considering the hurdles to successful GTx production and increasing efforts to
raise production, the US Food and Drug Administration (FDA) has provided
Drug Development for Gene Therapy: Translational Biomarkers, Bioanalysis, and Companion
Diagnostics, First Edition. Edited by Yanmei Lu and Boris Gorovits.
© 2024 John Wiley & Sons, Inc. Published 2024 by John Wiley & Sons, Inc.
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394
Table16.1 FDA guidance documents forindustry that provide recommendations
forvector testing, preclinical development, clinical trial design, and FDA approval ofgene
therapies.
Guidance document
Published
date
Final Guidance for Industry: Preclinical Assessment of Investigational
Cellular and Gene Therapy Products
Guidance for Industry: Expedited Programs for Regenerative Medicine
Therapies for Serious Conditions
Final Guidance for Industry: Human Gene Therapy for Retinal Disorders 2020
Final Guidance for Industry: Human Gene Therapy for Rare Diseases 2020
Final Guidance for Industry: Human Gene Therapy for Hemophilia 2020
Final Guidance for Industry: Long‐term Follow‐up After Administration
of Human Gene Therapy Products
Final Guidance for Industry: Chemistry, Manufacturing, and Control
(CMC) Information for Human Gene Therapy Investigational New Drug
Applications
Final Guidance for Industry: Testing of Retroviral Vector‐Based Human
Gene Therapy Products for Replication‐Competent Retrovirus During
Product Manufacture and Patient Follow‐up
Final Guidance for Industry: Interpreting Sameness of Gene Therapy
Products Under the Orphan Drug Regulations
Draft Guidance for Industry: Studying Multiple Versions of a Cellular or
Gene Therapy in an Early‐Phase Clinical Trial
Source: Adapted from FDA[1].
2013
2019
2020
2020
2020
2021
2021
guidance for industry regarding cellular and GTx products. Table16.1 highlights
some of the guidance documents (drafts and final guidances) related to the development and application of GTx published by the FDA.
In several of these guidance documents, the FDA refers to the development of a
CDx to detect antibodies against the human vector‐based GTx product to appropriately select patients for its clinical trial and to support market authorization.
However, there are currently no standards for manufacturers developing a CDx
product to select eligible patients for GTx trials. Therefore, CDx manufacturers
must design, develop, and validate these CDx assays to meet other published
standards (discussed in detail below). Another important resource in CDx development is the Q‐Submission program[2], which provides a mechanism for interactive feedback with the FDA on the important analytical verification and clinical
validation studies required for CDx approval through the premarket approval
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(PMA) process. By working closely with the FDA during a CDx’s development
and validation phases, the likelihood of a contemporaneous approval of that CDx
and its corresponding GTx increases–a critical factor for the success of patients
who will benefit from the GTx.
16.1.2 Summary of Validation Requirements for Gene Therapy
Companion Diagnostics (GTx CDx)
Like any other invitro diagnostic (IVD) regulated by the FDA, GTx CDx must follow analytical and clinical performance validation requirements. As mentioned
previously, the CDx claim for an assay requires PMA for commercialization since
assays with a CDx claim are of the highest risk type. Hence, these assays must follow FDA requirements per Clinical and Laboratory Standards Institute (CLSI)
Guidelines. However, because the studies required to validate a CDx under CLSI
guidelines are very thorough and time‐consuming, sponsors often choose to first
validate their product as Clinical Trial Assay (CTA) and meet FDA requirements
for submission as an Investigational Device Exemption (IDE), which requires less
rigorous validation than a PMA submission for a CDx. The laboratory conducting
these validations will need to assess performance of the CTA in accordance with
the Clinical Laboratory Improvement Amendments (CLIA) program prior to
CLSI validation studies.
IVD manufacturers typically take a two‐phase approach to validate the CDx:
First, they conduct an initial analytical validity performance assessment of a CTA
to ensure accurate and reliable test results where the initial analytical sensitivity
results can be used to collect safety and efficacy data. This is followed by clinical
data evaluation to select the clinical cutoff and to validate CLSI standards for final
IVD CDx configuration and use in the pivotal trial to allow patient selection or
stratification.
16.1.3 Role of CDx in Therapeutic Development and Unique
Challenges to Validating GTx CDx
Eligibility criteria for patients undergoing GTx can be evaluated based on expected
risks and potential benefits determined from preclinical studies. As a result, inclusion of patients with varying severities of disease should be considered carefully.
Healthy volunteers should be excluded from most GTx trials. Early‐phase GTx
trials may sometimes only enroll patients who do not have any other acceptable
treatment options. Additionally, patients who may have characteristics that influence the safety or efficacy of the therapy may also be excluded from trials, as these
can affect results[3].
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When used with GTx, a CDx can help inform treatment decisions. Thus, identifying the appropriate CDx has been proposed in multiple guidelines relevant to
gene therapy[4–6]. CDxs are often IVD devices that provide information essential
for safe and effective use of a corresponding drug or biologic.
A CDx can help identify patients who are likely to benefit from therapy or those
likely to experience treatment‐related adverse events. These tools may facilitate
the monitoring of treatment response, enabling healthcare providers to adjust
therapy and achieve improved safety or effectiveness [7]. A few examples of
approved CDxs include polymerase chain reaction kits to detect mutations in
patients and immunohistochemistry or enzyme‐linked immunosorbent assays to
detect protein expression related to disease or treatment. Current regulatory guidance recommends the development and use of CDx assays to assess not only GTx
safety but efficacy as well. For these uses, CDxs can be split into two categories:
● Tests used to confirm genetic disorders: For diseases caused by a genetic
defect, genetic testing should be performed. In the absence of a reliable, readily
available means of obtaining the necessary genetic diagnosis, a CDx may be
needed and should be considered early in development of the GTx[4].
● Tests to evaluate preexisting antibodies: To ensure the therapeutic potential
of a GTx product, sponsors should consider developing CDxs to detect total
antibodies (TAbs) and/or neutralizing antibodies (NAbs) in patient serum or
plasma. If CDxs are needed to appropriately select patients for clinical trials
and, ultimately, for treatment, then submission of the marketing application for
the CDx and the biologics license application for the GTx should be coordinated
to support contemporaneous marketing authorizations[4].
16.1.4 Key Considerations for Developing GTx CDx
Ideally, CDx development should occur in parallel with drug development[8]. As
with development of a CDx for any other type of drug, development of GTx CDx
should begin with a clear definition of the assay’s use, what it measures, and the
risks and benefits associated with it. In addition, it is important to define which
patient population(s) would benefit from use of the assay in conjunction with
therapy[8]. The investigational device exemption (IDE) for CDxs used in clinical
studies is based on level of risk in that the IDE regulation distinguishes between
nonsignificant and significant device risks[9]:
● IDE Exempt: CDx has no direct effect on treatment.
● Nonsignificant‐risk (NSR) Abbreviated IDE: A wrong result from the CDx does
not constitute a safety risk.
● Significant‐risk (SR) IDE: A wrong result from the CDx constitutes a safety risk.
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