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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5665_Библиотеки_им_академика_М_И_Перельмана
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References 407
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testing prospectively and also in downstream analytical validation studies or even
a bridging study if the final CDx is not used for testing in the pivotal study. The
stability of the banked samples needs to be shown over time and therefore, short‐
term and long‐term sample stability studies should be started during the CLIA
validation studies. This will support the sample handling during the trials and
storage of the samples over time.
16.7.2 Summary of Validation Considerations for CTAs/CDx to
Enable GTx Marketing
Following CLIA validation of the CTA, the next step is to conduct a performance
validation per CLSI guidelines of the final version of the CDx. This is a comprehensive set of studies meant to evaluate all components of assay performance.
Some of these studies will require clinical samples, and contrived sample panels
cannot be used, which again speaks to the importance of banking specimens. It
will also be critical to know the clinical cutoff at which to validate the assay’s
performance.
The goal of proper planning in assay development should be that the final version of the CDx is locked prior to the pivotal GTx study and that all CLSI validation is conducted prior to using the CDx in that study. Therefore, a bridging study
for inclusion in the PMA would not be required. Further, the CDx sponsor’s design
control documentation should address the design of the CDx from feasibility
through validation. Timing for reviews and requirements should be coordinated
across both CDRH and CBER to ensure contemporaneous approval of both submissions (PMA and BLA).
References
1 U.S. Food and Drug Administration (FDA) (2021). Cellular and gene therapy
guidances; Dec [cited 2022 Aug 24]. https://www.fda.gov/vaccinesbiologics/biologics- guidances/cellular- gene- therapy- guidances (accessed
28 September 2023).
2 U.S. Food and Drug Administration (FDA) (2021). Requests for feedback and
meetings for medical device submissions: the Q Submission Program; guidance
for industry and Food and Drug Administration staff; Jan [cited 2022 Aug 24].
https://www.fda.gov/media/114034/download (accessed 28 September 2023).
3 U.S. Food and Drug Administration (2015). Considerations for the design of
early‐phase clinical trials of cellular and gene therapy products; guidance for
industry. U.S. Food and Drug Administration. Center for Biologics Evaluation
blood-
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408
and Research; June [cited 2019Mar 11]. https://www.fda.gov/media/106369/
download (accessed 28 September 2023).
4 U.S. Food and Drug Administration (2020). Human gene therapy for rare
diseases; guidance for industry. Center for Biologics Evaluation and Research;
Jan [cited 2019Mar 11]. https://www.fda.gov/media/113807/download (accessed
28 September 2023).
5 U.S. Food and Drug Administration (2020). Human gene therapy for hemophilia;
guidance for industry. Center for Biologics Evaluation and Research; Jan [cited
2019Mar 11]. https://www.fda.gov/media/113799/download (accessed
28 September 2023).
6 U.S. Food and Drug Administration (2018). Human gene therapy for retinal
disorders; draft guidance for industry. Center for Biologics Evaluation and
Research; Jul [cited 2019Mar 11]. https://www.fda.gov/media/113814/download
(accessed 28 September 2023).
7 U.S. Food and Drug Administration (FDA) (2018). In vitro companion diagnostic
devices. https://www.fda.gov/regulatory- information/search- fda- guidancedocuments/in- vitro- companion- diagnostic- devices (accessed 27 September 2018).
8 U.S. Food and Drug Administration 2016 Principles for codevelopment of an
invitro companion diagnostic device with a therapeutic product; draft guidance
for industry and Food and Drug Administration staff. Center for Devices and
Radiological Health; Jul [cited 2022 Aug 24]. https://www.fda.gov/media/99030/
download (accessed 28 September 2023).
9 U.S. Food and Drug Administration (2020). IDE approval process; Nov [cited
2022 Aug 24]. https://www.fda.gov/medical- devices/investigational- deviceexemption- ide/ide- approval- process (accessed 28 September 2023).
10 U.S. Food and Drug Administration (2006). Significant risk and nonsignificant
risk medical device studies. https://www.fda.gov/regulatory- information/
search- fda- guidance- documents/significant- risk- and- nonsignificant- riskmedical- device- studies (accessed 06 September 2018).
11 U.S. Food and Drug Administration (2017). Investigational IVDs in therapeutic
product clinical investigations. Center for Devices and Radiological Health; Dec
[cited 2022 Aug 24]. https://www.fda.gov/media/109464/download (accessed
28 September 2023).
12 U.S. Food and Drug Administration (2006). Information sheet guidance for
sponsors, clinical investigators, and IRBs frequently asked questions statement of
investigator. https://www.fda.gov/regulatory- information/search- fda- guidancedocuments/information- sheet- guidance- sponsors- clinical- investigators- and- irbsfrequently- asked- questions (accessed 01 Feburary 2022).
17
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Regulatory Considerations forGene Therapy
Companion Diagnostics
Mica Elizalde1 and Paul Bartel
1
Regulatory Digital Health, Merck Sharp & Dohme LLC, Rahway, NJ, USA
2
Myriad Genetics, Companion Diagnostics, Salt Lake City, UT, USA
2
17.1 Introduction
Because of the critical role that companion diagnostics (CDx) play in the selection
of a patient’s therapeutic treatment, the development, approval, and maintenance
of these diagnostics is highly regulated in a number of markets. In this chapter,
the requirements for regulatory approval in the United States and (European
Union) EU will be covered in some detail, while other regulated markets (e.g.
United Kingdom, Japan, China) are noted but not covered in detail. The agencies
responsible for regulating CDx in several key markets are presented in Table17.1.
This chapter also includes discussion of topics such as global regulatory strategies, alternative CDx development strategies, commercialization, and CDx for
rare diseases. For overall review of the role of CDx in gene therapy and strategies
for CDx development and considerations for commercialization, see Chapter15:
Introduction to Companion Diagnostics for Gene Therapy.
409
17.2 US FDA
In the United States, the Center for Devices and Radiological Health (CDRH), a
branch of the Food and Drug Administration (FDA), is responsible for marketing
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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410
Table17.1 Regulation ofcompanion diagnostics inkey markets.
Market Regulatory agency
United States of America (US) Food and Drug Administration (FDA)
European Union (EU) Individual Member State National Competent
Canada Health Canada (HC)
United Kingdom (UK) Medicines and Healthcare products Regulatory Agency
Japan Pharmaceuticals and Medical Device Agency (PMDA)
People’s Republic of China
(China)
Authority
(MHRA)
National Medical Products Administration (NMPA)
authorization of CDx, as well as administering oversight of manufacturing, performance and safety of such devices. The FDA has issued guidance documents
including “Guidance for Industry: In Vitro Companion Diagnostic Devices” and
“Principles for Codevelopment of an In Vitro Companion Diagnostic Device with
a Therapeutic Product” to assist companies in the development of CDx[1, 2].
17.2.1 Clinical Trials forInvestigational Device Exemption
The Investigational Device Exemption (IDE) is the regulatory pathway for clinical
trials conducted in the United States that utilize a CDx. The IDE pathway defines
three types of device studies: exempt, nonsignificant Risk (NSR), or significant
risk (SR)[3]. It is the responsibility of the CDx manufacturer to determine the
study risk type that is applicable to their device. When making this assessment,
the manufacturer has the option to consult with the FDA by submitting a study
risk determination pre‐submission. The study risk determination process is a
request from the manufacturer to the FDA to determine if the clinical study would
be a SR, NSR, or exempt. The requirements of each IDE regulation risk status are
outlined below.
Exempt device studies do not have to follow the requirements listed in 21 CFR
812, with the exception of disqualification of clinical investigators from the study
(21 CFR 812.119)[4]. For a clinical trial to be considered an exempt device study,
the device must meet the requirements of 21 CFR 812.2(c):
● A device that was in commercial distribution prior to May 28, 1976 and is used
within its intended use.
● A device that has received FDA clearance or approval and is used within its
intended use.
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● A diagnostic device that,
○ Is noninvasive or does not require invasive sampling.
○ Does not introduce energy into a subject.
○ Is not used as a diagnostic procedure or is used with confirmation by another,
medically established diagnostic product or procedure.
○ Is undergoing consumer preference testing, testing of a modification, or test-
ing of a combination of two or more devices in commercial distribution.
● A custom device that is not being used to determine safety or effectiveness
If the manufacturer determines that use of their device in the study meets the
requirements of a NSR device study, the manufacturer and trial sponsor are
required to follow the abbreviated requirements for 21 CFR 812.2(b). This obligates them to the following:
● Label the device as investigational use only.
● Obtain and maintain institutional review board (IRB) approval of the investigation.
● Obtain informed consent for each patient in accordance with 21 CFR 50 and
21 CFR 56.
● Conduct monitoring of the device investigation.
● Maintain the records of the clinical trial, including adverse events records and
reports.
● Maintain and submit progress and final reports.
● Do not promote or commercialize the investigational device.
For a CDx that is being used in a therapeutic clinical trial, most of the abbreviated requirements are already being completed by or on behalf of the drug sponsor. What is worth noting is that these activities are typically conducted with the
therapeutic in mind and not necessarily with thought of the device. One consideration is that the informed consent document should also speak to the use of the
investigational device in the study, including any risks to the patient from the use
of the device. In addition, monitoring of clinical trial sites that are conducted by
the drug sponsor does not always include the clinical trial sites for the device.
If the manufacturer determines the device meets the definition of a SR study, or
the IRB does not agree with the manufacturer’s assessment of NSR, the full
requirements of 21 CFR 812 must be followed. This includes the additional
requirement of submission of an IDE application to the FDA. An IDE application
includes elements such as:
● Device description
● Analytical validation studies
● Information regarding previous clinical studies
● Description of the manufacturing process
● Risk summary of the device
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412
● Labeling material
● Investigator and clinical site information
Once the IDE application is submitted, the FDA has 30days to approve, conditionally approval, or reject the application. If approval is granted, the manufacturer can
initiate the clinical trial once IRB approval is received. If the FDA grants a conditional approval, the manufacturer can still initiate the clinical trial once IRB approval
is received; however, they will have to fulfill the additional requests received in the
conditional approval letter. These requests could be additional validation studies,
updates to labeling, or responses to information requests. If rejected, the manufacturer cannot initiate the clinical trial and the manufacturer must remediate any concerns identified by the FDA and resubmit the application once resolved.
Interventional clinical trials for AAV‐mediated gene therapies that utilize a CDx
will typically be considered either NSR or SR. Some questions that should be
assessed would be:
● Is the sample collection process invasive? Some testing only requires blood col-
lection, while others may require a fresh biopsy to be collected within certain
time limits.
● What is the risk to the patient in the event of a false positive or false negative?
For patients that would be enrolled in the study based on the potentially
false result, an overview and understanding of the risks associated with
AAV‐mediated gene therapy will be necessary to assess the patient risk. This
includes treatment of emergent adverse events (TEAE) and immune‐related
adverse events (irAE). For patients who would not be enrolled in the study
based on the potentially false result, an understanding of the existing treatment
options that would be available to them would be necessary.
● What are the risks that enrolled patients will be exposed to? Similar to the dis-
cussion points in the above bullet on false‐positive or false‐negative results, an
understanding of the risks that enrolled patients will be exposed to during the
trial compared to standard of care treatment options must be considered in
understanding the full risk profile of the CDx during the trial.
● How will the health care professional (HCP) monitor the patient during the
clinical trial and will the patient continue to receive the same standard of care
that they did prior to receiving the investigational treatment? HCPs that may
continue to offer other treatment options to their patient during the trial may
help to offset the device study risk status. Conversely, patients who must cease
all other treatment or care options before, during, or after treatment with the
AAV‐mediated gene therapy may pose an increased device study risk status.
For more information on evaluating risks for a CDx in a clinical trial or understanding the differences between NSR or SR, refer to FDA draft guidance
Investigational IVDs Used in Clinical Investigations of Therapeutic Products[5].
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17.2.2 US FDA Marketing Authorization Pathways
CDx seeking marketing authorization in the US has two primary regulatory pathways that can be followed based on the classification of their device: Premarket
Notification 510(k) or Premarket Approval (PMA). For programs that are seeking
approval for a rare disease indication, a Humanitarian Device Exemption (HDE)
authorization is an additional option that can be used and is explained below.
17.2.2.1 510(k) process
The 510(k) process is the marketing authorization pathway for non‐exempt
Class I and Class II invitro diagnostics devices[6]. This process requires the manufacturer to demonstrate to the FDA that the device is as safe and effective as a
predicate device. This is referred to as demonstrating substantial equivalence. The
FDA defines a predicate device as a legally marketed device that is:
● A device that was placed on the market prior to May 28, 1976, referred to as a
pre‐amendment device.
● A Class I or Class II device that has already demonstrated and shown substan-
tial equivalence through the 510(k) process or was approved and reclassified as
Class I or Class II through the de novo process.
Substantial equivalence is demonstrated by the manufacturer by showing that their
device has the same intended use as the predicate device and has the same technological characteristics as the predicate. If the device does not have the same technological
characteristics as the predicate, then the device must be as safe and as effective as the
predicate device. The contents of a 510(k) application include items such as:
● Device description
● Comparison of the subject device to the predicate device
● Performance specification and testing results
● Labeling
● Shelf life of the device
● Performance testing and results
At the end of the 510(k) process, the FDA will determine if the device is substantially equivalent (SE) to the predicate device. If SE is demonstrated, the device
will receive clearance and will be able to be commercially marketed once the
clearance has been issued. This will also allow the device to be used as a predicate
device for future submissions. FDA typically provides its SE determination within
90days; however, this timeline can be extended if the FDA determines they need
additional information and place the review on hold. Premarket inspection of a
device manufacturing facilities is not typically required for a 510(k) review and SE
determination, though the manufacturer will be subject to FDA quality system
inspections after receiving 510(k) clearance.
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414
17.2.2.2 PMA Process
For Class III devices, a manufacturer must submit a PMA application to the
FDA[7]. A PMA goes through a formal review and approval process with the
FDA, similar to a New Drug Application (NDA) or Biologics Licensing Agreement
(BLA). The PMA process is the most robust device review process at the FDA. The
manufacturer must demonstrate that the device is both safe and effective for the
patient population based on its intended use. Due to the large amount of information included in a PMA, most information submitted in a PMA falls into one of
the five sections. FDA has also issued a number of PMA guidance documents
including “Premarket Approval Application Modular Review”[8] and “Acceptance
and Filing Reviews for Premarket Approval Applications (PMAs)”[9].
● Administrative information supporting the application, such as device descrip-
tion, summary of the contents, marketing history, and financial declarations.
● Quality system information showing the device meets the requirements of the
quality system regulation, 21 CFR 820.
● Nonclinical studies, both a summary of what was completed and the complete
test protocols, plans, and reports.
● Clinical study overview that demonstrates the studies were completed in
accordance with the relevant IDE requirements, conclusions of safety and effectiveness, and complete line data from the studies.
● Software information should also be included if the device is or contains soft-
ware components that are required for the device to operate as intended.
At the end of the PMA process, if approved, the FDA will issue either an
approval letter or an approvable letter. An approval letter is issued based on draft
labeling and the device is approved on the condition that the manufacturer submits final labeling before marketing the device. An approvable letter means that
the device substantially meets the requirements for approval and FDA believes
they can approve the device if specific information is supplied by the manufacturer to FDA or specific conditions are agreed to by the manufacturer. FDA typically provides its approval determination within 180 days from submission;
however, this timeline can be extended if the FDA determines they need additional information and place the review on hold.
17.2.2.3 HDE Process
An HDE application can be used for devices that are intended for rare disease
populations, a rare disease being defined by the Orphan Drug Act of 1984 as
“a disease or condition that affects fewer than 200,000 people in the United
States”[10]. An HDE application is most similar to a PMA application, with a few
exceptions, most notable is that an HDE is exempt from the requirements of demonstrating effectiveness [11]. Because of this, devices approved by HDE are
17.2 US FDA 415
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required to contain a statement in their labeling stating that the effectiveness of
the device has not been demonstrated. Two other important considerations when
determining an HDE authorization are: their eligibility for profit and the continual monitoring of the device’s Annual Distribution Number (ADN).
Devices authorized under the HDE pathway cannot be sold for profit, or for an
amount that exceeds the cost of research, development, production, and distribution. If the device is priced above $250, a report by an independent certified public
accountant or an attestation by a responsible individual of the organization verifying the cost is required to be submitted to the FDA. There are two exceptions to
this rule that are outlined under section520(m)(6)(A)(i) of the FD&C Act:
● The device is intended for the treatment or diagnosis of a disease or condition
that occurs in pediatric patients or in a pediatric subpopulation, and such device
is labeled for use in pediatric patients or in a pediatric subpopulation in which
the disease or condition occurs; or
● The device is intended for the treatment or diagnosis of a disease or condition
that does not occur in pediatric patients or that occurs in pediatric patients in
such numbers that the development of the device for such patients is impossi-
ble, highly impracticable, or unsafe.
As only devices that are intended for rare disease populations are eligible for
the HDE pathway, the total number of devices sold must stay below the FDA‐
determined ADN for the device. The ADN is typically 8,000 devices which assumes
one device is needed to treat, diagnose, and/or cure one patient. However, if more
than one device is needed, then the ADN will be increased accordingly. The HDE
holder is required to monitor the number of devices sold per year and report this
to the FDA in their periodic report, also known as an annual report. If the number
of devices sold exceeds the established ADN, the HDE holder is required to immediately notify FDA. If at any point after obtaining an HDE authorization the disease status changes and is no longer considered a rare disease, the HDE holder
will need to submit and receive a PMA authorization in order to keep their device
commercially available.
17.2.2.4 Differences Between 510(k) and PMA
Some differences in review between a 510(k) and PMA are the level of detail and
information that is expected to be included in the application. While both pathways
have an expectation for nonclinical performance data, the PMA submission is
required to include the test protocols and full testing reports that include testing
results, discussion, and a summary of any testing deviations that occurred. A 510(k)
submission may not be required to have conducted a clinical study, while a PMA
application has the requirement for clinical data with the expectation of a statistical
analysis to be completed and the full line data for the study to be supplied.
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416
A PMA will also include a premarket inspection of the submitter’s facility to verify
the device was developed in accordance with the quality system regulation, 21 CFR
820. This inspection is scheduled after the review of the quality system portion of
the application is completed and all outstanding questions have been resolved.
17.2.3 US FDA Pre-submission Feedback
During the CDx development process, the manufacturer has the option to seek feedback from the FDA on their device by submitting a Pre‐Submission Request[12].
A Pre‐Submission, referred to as a Pre‐Sub, is a formal written feedback request
from the CDx manufacturer to the FDA to solicit feedback. During the written
request, the manufacturer can request to schedule a 1‐hour meeting with the
agency, to take place after the receipt of the formal feedback. All interactions during
the Pre‐Sub, requests, briefing materials, feedback, and meeting minutes, are documented and retained to guide for future interactions, submissions, or applications.
The Pre‐Sub process is entirely voluntary, but it is highly recommended that it be
utilized. Through a Pre‐Sub, the manufacturer can reach agreement with the
agency on topics such as analytical validation, clinical validation, requirements for
an IDE or PMA application, classification, or labeling. For a Pre‐Sub, the manufacturer will submit a cover letter and briefing book to the agency. The cover letter will
contain the manufacturer’s contact information, method of feedback (written feedback only or written feedback followed by a meeting), dates and times of the meeting (if requested), purpose of the Pre‐Sub, device description, or intended use. The
briefing book will contain the relevant information that is necessary to obtain useful and thorough feedback from the agency. A first Pre‐Sub request for a device
may contain a detailed summary of the device, prospective patient population, and
intended disease area, in addition to relevant information pertaining to the questions being asked by the reviewers. Conversely, Pre‐Sub requests that are following
up on previous interactions may contain the device’s intended use statement with
a summary of any pertinent changes before going into information specific to the
questions and/or topics being addressed. For more information regarding Pre‐
Subs, including example questions, refer to FDA guidance Requests for feedback
and meetings for medical device submissions: The Q‐Submission Program[12].
17.3 European Union
17.3.1 European Union Clinical Trials
In 2017, the EU released Regulation (EU) 2017/746 invitro diagnostic regulation
(IVDR) [13]. The IVDR sets out requirements for in vitro diagnostics in the
EU. This includes invitro diagnostics that are performed ex‐EU for which results
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