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also need to be evaluated as part of genotoxicity risk assessment. The traditional
cytogenetic tests (karyotyping and FISH) can be conducted in compliance with
the agency guidelines and are still the gold standard to provide information on
structural and numeric chromosome aberrations. Recently, developed NGS‐based
techniques offer better sensitivity and granularity of DNA sequences at translocation sites. These molecular methods are expected to gain broader use to complement cytogenetic testing.
14.4 Concluding Remarks
Genome editing technologies are evolving rapidly with multiple studies being carried out in the clinic. Recent advances in detecting on‐ and off‐target editing help
to characterize the efficacy and safety of genome editing tools. Safety assessment
includes orthogonal evaluation of off‐target activities encompassing short indels,
large deletions and insertions as well as chromosome translocations. We will continue to learn about the mechanisms and factors affecting the occurrence of these
off‐target effects and how best to detect these molecular events. Recent regulatory
guidance from US FDA and the EMA provides scientists and drug developers
insight into assessing safety, quality, and potential risks for therapies utilizing
engineered nucleases. These engineered nucleases offer great promise for treating
acquired and genetic diseases, thus underline the importance of these evolving
molecular methods as part of safety and risk assessment for patients.
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Section IV
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Companion Diagnostic Development forGene Therapy
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15
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Introduction
toCompanion Diagnostics forGene
Therapy
Paul Bartel1 and Jennifer Granger
1
Companion Diagnostics, Myriad Genetics, Inc., Salt Lake City, UT, USA
2
PharmaDx, ARUP Laboratories, Salt Lake City, UT, USA
2
15.1 Introduction toCompanion Diagnostics
A companion diagnostic (CDx) is a medical device that is required by regulatory
agencies to determine patient eligibility for a drug or biological product[1]. Most
often, a CDx is used to identify patients who are likely to benefit from treatment
with a particular therapeutic. CDx products are invitro diagnostics (IVD), which
the Food and Drug Administration (FDA) defines as the reagents, instruments,
and systems intended for use in diagnosis of disease or other conditions. They
may be used in a manner to cure, mitigate, treat, or prevent disease. In the United
States, CDx are typically categorized as Class III in vitro diagnostics (CDx are
Class C in the EU), which is the highest risk category. As such, a CDx will require
premarket approval (PMA) prior to full commercial marketing.
The concept of a CDx was introduced through the approval by the US Food and
Drug Administration (FDA) of the HER2 assay for the drug trastuzumab in
1998[2]. However, it was not until later in 2014 when the FDA issued “Guidance
for Industry: In Vitro Companion Diagnostic Devices”[3] that the FDA more formally recognized the CDx. This guidance document was intended to assist pharmaceutical companies with an early assessment of the need for a CDx, i.e. during
the drug development process, with the intention of CDx and therapeutic
co‐development offering more rapid access to treatments for patients.
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.
15 Introduction toCompanion Diagnostics forGene Therapy
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386
Other regulatory agencies have also recognized the need for companion diagnostics including the European Medicines Agency (EMA), which introduced the
In Vitro Diagnostic Devices Regulation (IVDR) that included a new classification
system for CDx in 2017[4], and the Pharmaceuticals and Medical Devices Agency
(PMDA) of Japan, which published a “Notification on Approval Application for
In Vitro Companion Diagnostics and Corresponding Therapeutic Products”[5] in
2013 defining a CDx as an invitro diagnostic reagent or device essential for the
safe and effective use of corresponding therapeutic product.
The following sections describe the role of the CDx in gene therapy, strategies
for CDx development, and considerations for their commercialization. In addition, Chapters 16 and 17 provide additional details on the validation and regulatory considerations for CDx development, respectively.
15.2 Role inGene Therapy
CDx have been used to ensure the best chance of success through a personalized
medicine approach to choosing the appropriate drug for a given target population[6]. To date, over 50 companion diagnostic devices have been approved by the
US FDA, the majority of which are intended for indications within the oncology
space[7]. In rare instances, the FDA has also approved cancer therapeutics with
so‐called complementary diagnostics, which are defined as diagnostics that may
predict a more favorable benefit ratio but which are deemed non‐essential due to
the overall drug benefit (Progression Free Survival [PFS], Overall Survival [OS])
within the indication[6].
The requirement for CDx tests has recently begun to expand beyond oncology
as gene therapy (GTx) emerges as a promising new approach in personalized medicine with the potential to cure inherited disorders with a single treatment. GTx
functions at the molecular level by introducing therapeutic genes into target cells
using a delivery vehicle, or vector. Vectors can be non‐viral, such as those found in
DNA and mRNA strategies, or viral, which are typically recombinant viral vectors
that are unable to replicate in the host cell[8].
One of the most promising classes of viral vectors currently being developed for
GTx is the adeno‐associated virus (AAV)[9]. However, since AAVs are endemic to
the human population, the determination of pre‐existing immunity against an
AAV GTx is essential for patient safety and drug efficacy. In current GTx clinical
trials, early bioanalytical methods are largely being utilized to identify patients
with higher levels of preexisting immunity against a specific vector that could
neutralize the corresponding drug product and reduce the level of efficacy.
Seroprevalence studies (as discussed in Chapter 6: Bioanalytical Methods to
Detect Pre‐existing and Post‐administration Humoral Immune Responses Against
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