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Regulatory considerations for companion diagnostic devices

The emergence of companion diagnostic devices has been spurred by drug discovery and development efforts towards targeted therapies, particularly in oncology. Companion diagnostics and their corresponding therapeutics are often codeveloped, or developed in parallel, to ensure the safe and effective use of the products. The regulatory framework for companion diagnostics has gradually evolved as a result of the essential role of diagnostic tests to identify the intended population for a corresponding treatment. Here, we describe the current regulatory model for companion diagnostics in the US and outline key strategies for a successful codevelopment program from the device perspective. We also discuss how technological advances and changes in clinical management may challenge the regulatory model in the future.

Eunice Y Lee*,1 & Hsin-Chieh Jennifer Shen*,1 Division of Molecular Genetics & Pathology, Office of In Vitro Diagnostics & Radiological Health, Center for Devices & Radiological Health, US FDA, 10903 New Hampshire Avenue, Silver Spring, MD 20993, USA *Authors for correspondence: [email protected] [email protected] 1

Keywords:  assay • biomarker • codevelopment • in vitro companion diagnostic • medical device • personalized medicine • precision medicine • regulation

Personalized medicine, or precision medicine, is a rapidly growing field that employs an evidence-based, individualized approach to tailor the right care to the right patient at the right time [1] . The development of targeted therapies is dependent upon the identification of clinically relevant biomarkers, such as DNA mutations or protein overexpression. Biomarkers may serve as the targets against which therapeutic products are designed, and they may be used to identify the intended patient population. Examples of such intended patient populations are those who may benefit from a treatment, those who should not receive a treatment or those who may be harmed by a treatment [2] . The presence, absence or amount of appropriate biomarker(s) is critical for the safe and effective use of a targeted treatment, and therefore necessitates the development of companion diagnostic devices. As a result, codevelopment of targeted therapeutics and companion diagnostic devices is a cornerstone of ­personalized medicine. The regulatory rationale for codevelopment products has gradually evolved based

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on the available scientific knowledge and technology over the course of time. Diagnostics have long been an important tool for clinicians; however, as the drug development model shifted to personalized medicine and devices took on a central role to guide patient treatment, the need for a regulatory structure for companion diagnostics became evident. The first codevelopment products, trastuzumab and a HER2 immunohistochemistry (IHC) assay, were approved in 1998 by the US FDA [3,4] , when it was shown that knowledge of biomarker status was critical for using the biologic in a safe and effective manner. As pharmacogenomics became increasingly employed and its enormous potential impacts were realized, efforts towards developing regulation for codevelopment products were initiated. A series of public meetings were held from 2002 to 2005 to bring together experts, regulators and other interested stakeholders to discuss relevant issues and gain public input [5–7] . In 2005, the FDA issued a preliminary concept paper describing a regulatory approach for companion diagnostics [7] . Subsequently, a draft guidance document

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Table 1. List of US FDA-approved or -cleared companion diagnostics and corresponding oncology therapeutic products. Clinical indication

Drug trade name (generic name)

Device trade name

Technology

Breast cancer

Herceptin (trastuzumab)

INFORM HER2/neu

FISH

 

PathVysion HER2 DNA Probe Kit

FISH

 

PATHWAY anti-HER2/neu (4B5) Rabbit Monoclonal Antibody

IHC

 

InSite HER2/neu Kit

IHC

 

SPOT-Light HER2 CISH Kit

CISH

 

Bond Oracle HER2 IHC System

IHC

 

HER2 CISH PharmDx Kit

CISH

 

INFORM HER2 Dual ISH DNA Probe Cocktail

ISH

Breast cancer, metastatic gastric cancer or gastroesophageal junction adenocarcinoma

Herceptin (trastuzumab), Perjeta (pertuzumab)

HercepTest

IHC

Kadcyla (ado-trastuzumab emtansine)

HER2 FISH PharmDx Kit

FISH

Colorectal cancer

Erbitux (cetuximab)

therascreen KRAS RGQ PCR Kit

PCR

Vectibix (panitumumab)

EGFR PharmDx Kit

IHC

Gastrointestinal stromal tumor

Gleevec/Glivec (imatinib mesylate)

C-KIT PharmDx

IHC

Melanoma

Mekinist (tramatenib), Tafinlar (dabrafenib)

THxID BRAF Kit

PCR

Zelboraf (vemurafenib)

cobas 4800 BRAF V600 Mutation Test PCR

Gilotrif (afatinib)

therascreen EGFR RGQ PCR Kit

PCR

Tarceva (erlotinib)

cobas EGFR Mutation Test

PCR

Xalkori (crizotinib)

Vysis ALK Break Apart FISH Probe Kit FISH

Non-small-cell lung cancer

CISH: Chromogenic in situ hybridization; IHC: Immunohistochemistry.

on in vitro companion diagnostic devices was released in 2011, and final guidance was published in 2014 [2] . As scientific knowledge continues to accumulate and as new technologies emerge, the current paradigm for companion diagnostics may also continue to evolve in order to address new challenges that may be ­encountered. From approvals of the first codevelopment products to the most recent drug and diagnostic coapprovals in 2014, the FDA has accumulated experience to streamline the regulatory review process, as well as to develop policies and procedures for companion diagnostic devices. This article will discuss drug–diagnostic codevelopment from the device perspective, focusing on the US regulatory framework for companion diagnostic development. An overview of the FDA-approved companion diagnostics will be provided, highlighting key considerations for codevelopment programs. This article will also briefly touch on the challenges associated with current advances in high-throughput technologies and clinical trial designs that have the potential to impact the codevelopment regulatory program.

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Regulatory model for companion diagnostics According to the FDA guidance document titled ‘In Vitro Companion Diagnostic Devices’, a companion diagnostic is defined as a device that provides information that is essential for the safe and effective use of a corresponding therapeutic product [2] . Accordingly, the general coapproval regulatory model of ‘one drug, one test’ traditionally involves the approval of a single companion diagnostic device for a specific biomarker, such as HER2 protein expression or EGFR mutations, together with the approval of a corresponding therapeutic for a specific indication. Furthermore, the labeling for each codeveloped product should specify that the product is indicated for use with the corresponding product, or type of product, in the case of the diagnostic device [2] . The drug will be named in the device labeling and reference is made to the type of device in the package insert for the drug. The companion diagnostic devices that have recently been cleared or approved by the FDA have followed this model, whereby each device has been

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reviewed in conjunction with a corresponding therapeutic product. The FDA has gathered practical experience in the review and approval of molecular companion diagnostics over the last 16 years. The FDA has granted marketing authorization for a total of 18 companion diagnostic devices indicated for therapeutics in oncology (Table 1) [8] . More than half of the approved molecular companion diagnostics are assays for the detection of HER2 expression or amplification in breast and gastric cancer. All of these companion diagnostic approvals involve using the device–drug pairs, such that cancer patient survival has improved for certain cancer indications (an up-to-date listing of currently approved or cleared companion diagnostic devices and the ­corresponding therapeutics may be found at [8]). In general, the premarket regulatory pathway for a companion diagnostic device is determined by the classification of the device. There are three medical device classifications – classes I, II and III – which are based on the ‘intended use’ of the device and the risk that the device poses to the patient and/or user [9] . As the risk increases, the classification and the regulatory controls increase [10] . To date, all companion diagnostics indicated for oncology therapeutics detect molecular targets. The ‘intended use’ of these approved companion diagnostic devices are associated with the ‘indication and usage’ of the corresponding oncology therapeutics. The risk associated with these companion diagnostics is that incorrect test results are likely to adversely affect clinical management and treatment decisions for these cancer patients [2] . All of the approved companion diagnostic devices that are indicated with oncology therapeutic products are classified as high-risk, class III devices and required Premarket Approval (PMA) applications to obtain marketing approval under section 515 of the Federal Food, Drug and Cosmetic Act [11] . One companion diagnostic device – an MRI system – is a moderate-risk, class II device under the Code of Federal Regulations (CFR) 892.1001 and was subject to the de novo classification process under section 513(f) of the Federal Food, Drug and Cosmetic Act [12,13] . Notably, the device is not a molecular oncology assay. Regardless of the regulatory premarket pathway, a companion diagnostic should be authorized in p ­ arallel with the corresponding therapeutic product [2] . Codevelopment strategies Although each codevelopment program may vary widely and be accompanied by unique challenges, general aspects and practices may be identified from the FDA’s previous experiences with the review and approval of companion diagnostic products. Most of the FDA’s insight and experience has been with

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molecular-based companion diagnostics in oncology, which have required PMA applications. The general principles and approaches described here will be widely applicable to similar types of companion diagnostics and premarket submissions. Taken together, these have shaped working processes for the review of companion diagnostic premarket submissions and provide the basis for current regulatory policies in the fast-moving field of personalized medicine. Alignment of regulatory review timelines

There have been numerous publications and public presentations outlining the codevelopment process for a device and its corresponding therapeutic product. Perhaps less transparent is the FDA regulatory review process once the corresponding applications are submitted. One important consideration is that the therapeutic product and its associated companion diagnostic are reviewed by different FDA Centers. The therapeutic products are reviewed at either the Center for Drug Evaluation and Research (CDER) or the Center for Biologics Evaluation and Research (CBER), while the companion diagnostics are reviewed by the Center for Devices and Radiological Health (CDRH) or potentially by CBER, which regulates a small number of diagnostic devices. As a result, the respective codevelopment applications are subject to relevant drug, biologic and device regulations, which are not necessarily well aligned. To achieve contemporaneous approvals of a therapeutic product and a companion diagnostic, review of the respective submissions requires a great deal of coordination and communication between the Centers. The FDA has developed efficient internal mechanisms to coordinate review activities across the Centers, as well as between the review divisions. These include an intercenter consult process, which entails coattendance of review staff at internal and external meetings, crossCenter input on related submissions (e.g., Pre-Submissions in CDRH or Investigational New Drug [IND] applications in CDER) and coordination of submission timelines for review and approval. This internal mechanism significantly facilitated contemporaneous approvals of four companion diagnostic devices with their respective therapeutic products in 2013 and 2014. For all drug–device coapprovals, the FDA has followed the regulatory review timeline of the lead therapeutic product center, either CDER or CBER. Thus, the initial projected review timelines will depend on the therapeutic submission types (e.g., original vs supplemental New Drug Applications [NDAs] or Biologics License Applications [BLAs]) [14] and the regulatory status of the submission (e.g., accelerated approval, priority review or need for an advisory committee meeting) [15] . In addition, if significant deficiencies are iden-

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Review  Lee & Shen tified during the course of the FDA therapeutic product review, then the projected review timelines may be modified and realignment across the Centers would be needed. Due to the different variables that can affect the review processes, the time frames from premarket submission to approval for device submissions have ranged from 3 months to almost 3 years. Despite this wide window, all of the companion diagnostic devices to date have been approved ­simultaneously with a corresponding therapeutic product. In much the same way that communication between the different review Centers at the FDA is critical, communication between the different product sponsors is necessary for a codevelopment program to succeed. Both the therapeutic and companion diagnostic sponsors are responsible for aligning the product development and submission timelines. It is often beneficial for sponsors to invite their codevelopment partner(s) to attend their respective meetings with the FDA to ensure that each party is aware of issues that may affect the review and approval processes. In addition, each sponsor is responsible for providing relevant and timely information to the respective FDA review divisions. It is the responsibilities of the sponsors to ensure that submission of the respective premarket applications are appropriately timed to allow for an efficient review process and contemporaneous approvals. Another key to achieving timely approval of a companion diagnostic is early communication between the codevelopment product sponsors and the appropriate CDRH review divisions through the Pre-Submission program (prior to the implementation of the Medical Device User Fee Amendments of 2012 [MDUFA III], the process was referred to as the pre-Investigational Device Exemption [IDE] program) [16,17] . The Pre-Submission program provides an opportunity for sponsors to receive FDA feedback regarding plans for a drug–device codevelopment program, which may include validation study designs, premarket submission pathways and timelines [16] . For instance, companion diagnostic sponsors could request FDA input on whether or not a bridging study protocol includes comprehensive assessment of the device performance. Companion diagnostic sponsors can also inquire about the appropriate regulatory strategy if they are developing a new indication for a previously approved companion diagnostic device or if they are engaged in a partnership with multiple therapeutic sponsors. Sponsors may also request study risk determinations for investigational trials that involve the use of a companion diagnostic device. Sponsors for most of the recently approved companion diagnostic devices from 2011 to 2014 had several Pre-Submission (or pre-IDE) interactions with CDRH, which facilitated the alignment

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of the expectations for the premarket submission from both the device manufacturers and the FDA. Modular PMA process

The realization of the need for a companion diagnostic may occur relatively late in the development of a therapeutic program. This could result in delays to the therapeutic product due to unexpected requirements related to the development of the device. Although submissions for companion diagnostics are granted expedited review, the submission timeline for a traditional PMA may still be a constraint. As outlined in 21 CFR 814.20, the FDA requires that all components of a traditional PMA be submitted at one time [18] . However, there is an alternative approach – the modular PMA process – that may aid device sponsors who may not be able to prepare all of the necessary information within a specified timeframe or who wish to begin review of certain parts of the PMA at an earlier time point than would be possible with a traditional PMA. The modular PMA allows for flexibility since discrete modules – or sections – of a traditional PMA may be submitted at different times [19] . The advantage of the modular PMA process is that a device sponsor may submit analytical data, manufacturing information and other PMA requirements prior to the submission of the clinical data. This allows for some device-related information to be reviewed while the collection, compilation and analysis of the clinical data (usually from one or more therapeutic product clinical trials) are ongoing. When the analysis of the clinical data is complete, the data are submitted as the final module of the PMA, which then converts the modular PMA to a traditional PMA. The benefit of the modular PMA mechanism is that it affords the sponsor the opportunity to resolve deficiencies related to earlier modules (i.e., those submitted prior to the final module) and thus maximizes the likelihood that the PMA review will be completed concurrently with the review of the corresponding therapeutic product. Another consideration is that sufficient time must be allowed for scheduling preapproval inspections. A key element of a PMA submission is demonstration of compliance with the quality system regulations for medical devices [20] . This ensures that products are designed in a controlled manner and manufactured consistently to meet specifications and applicable requirements. Typically, a preapproval quality system regulation inspection may be scheduled only upon satisfactory review of the quality system and manufacturing information submitted to support the PMA application. Completion of the manufacturing review and field inspection could potentially delay full approval of a PMA, and therefore the manufacturing module is often submitted

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as an early module when the modular PMA approach is utilized. Similarly, evaluation of a PMA application may require a bioresearch monitoring (BIMO) audit. This is a separate inspection from the preapproval manufacturing inspection, which is aimed at ensuring the quality and integrity of the data provided in the premarket submission [21] . If a BIMO inspection is needed, PMA applicants should assemble and submit the BIMO information as early as possible during the modular submission process to avoid any delays. The bulk of the BIMO information would generally be submitted with the clinical data in the final module. However, the sponsor may submit the available BIMO documentation prior to receipt of the clinical information. Although the clinical outcome data may not be available, items such as the clinical protocol, a list of clinical enrollment sites and investigators and the informed consent form template could be submitted earlier. Additional timing issues may arise when the facilities for inspection are located outside the US, because ­foreign inspections may require more time to schedule. Taken together, potential delays to the traditional PMA process for companion diagnostics may be circumvented through early planning and utilization of the modular PMA process. One example of the efficiency of the modular PMA mechanism is described here. A companion diagnostic sponsor worked closely with the CDRH review division during an early phase of product development and decided on the modular PMA approach. By the time the NDA and the final PMA module were submitted to CDER and CDRH, respectively, the CDRH review division had completed review of the manufacturing, software and analytical validation modules. Modular submission of the manufacturing information had allowed the review division to determine that re-inspection of the manufacturing facility was unnecessary for the new device, since the facility had been recently inspected with no findings. BIMO information had been submitted 3 months prior to submission of the last PMA module, allowing ample time for the BIMO inspection assignment to be issued and coordinated with field inspectors. As a result, the BIMO inspection at the clinical sites was completed within 1–2 months after conversion of the submission to a traditional PMA. Similarly, the analytical validation data were reviewed in a timely manner, such that all deficiencies were resolved by the time the sponsor sent the last PMA module. The sponsor’s careful management of the process and timelines allowed the CDRH review division to coordinate with the CDER review division to approve the products in parallel within the projected, shorter-than-usual 6-month timeline of the NDA.

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Validation of companion diagnostic devices To support approval (or clearance) of a companion diagnostic device prior to entering the US market, valid scientific evidence is required to support the safety and effectiveness of the device [18] . Validation studies for a device can be divided into two major categories: one is the analytical (measurement) performance validation of the companion diagnostic; and the other is the clinical performance validation. Depending on the design and principles of operation of the device, as well as the intended use, the types of analytical studies needed to support a premarket application vary. The clinical validation for companion diagnostic devices is typically supported by the therapeutic clinical trial results, such that the diagnostic test results are correlated with the therapeutic outcome. Together, the analytical and clinical validation studies should ensure that the device is accurate and reliable for the claimed intended use(s). Analytical validation

If a companion diagnostic device is composed of several components, it is important that analytical validation be conducted for the entire test system. The system may include the instrumentation and software that are utilized for result generation and analyses, as well as the preanalytical steps and reagents to prepare the analyte(s) for measurement. Preanalytical procedures may include tissue fixation, nucleic acid extraction, melanin removal and nucleic acid amplification or modification, among others. For example, if a companion diagnostic device is an IHC-based assay designed to assess formalin-fixed, paraffin-embedded clinical specimens, then preanalytical validation would be expected to include assessment of different fixation conditions, such as duration or temperature, to show how these preanalytical variables may affect assay performance. If a companion diagnostic device is a PCR assay utilizing DNA extracted from formalin-fixed, paraffin-embedded clinical specimens, then the DNA extraction method(s) that would be used as part of the companion diagnostic should be validated to ensure consistent assay performance. If a companion diagnostic device is to be utilized on multiple instrumentation platforms (e.g., different autostainer systems), each of the instrument platforms should be validated for use with the companion diagnostic assay. Thus, validation of a companion diagnostic should encompass the procedure from sample preparation to result reporting. The robust and reliable performance of a device is supported by analytical validation studies. In general, the analytical sensitivity and specificity of the device should be defined, as well as the performance

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Review  Lee & Shen parameters for reproducibility, precision and accuracy. The stability of the intended specimens and reagents should also be assessed and established. Importantly, analytical validation studies necessary to demonstrate the performance of a device may vary depending on the device description, technology and intended use. For example, a sample carryover study would be expected for a PCR-based assay that utilizes a multiwell plate format; however, this would not be applicable for a manual IHC-based test. It is essential to understand the critical aspects of analytical performance characteristics, and the Pre-Submission process described above is a mechanism by which sponsors may receive FDA input regarding the appropriateness of validation plans for companion ­d iagnostic devices. Clinical validation

The clinical performance of a companion diagnostic device is typically derived from the registrational therapeutic clinical trial results, which also support the NDA or BLA for the corresponding therapy [2] . In some cases, the final to-be-marketed device may not have been used in the registrational study(ies). If a prototype test, or clinical trial assay (CTA), is used to define the eligibility criteria or other critical selection or management criterion for the study population in the trial, then a bridging study demonstrating equivalent performance of the to-be-marketed device to that of the CTA would likely be needed in order to demonstrate that the to-be-marketed companion diagnostic device is safe and effective for its intended use. Ideally, all of the clinical specimens that were tested with the CTA would be retested with the to-be-marketed device in the bridging study, and the clinical trial data would be reanalyzed based on the test results from the ­companion diagnostic. If a bridging study is necessary, there are multiple sources of evidence that should be considered to demonstrate the effectiveness of a to-be-marketed device. This includes the observed effectiveness of the CTA, the assessment of concordance and discordance between the results from the CTA and the final companion device and the effects of missing data (in the event that all of the originally tested samples cannot be retested with the to-be-marketed device). A successful bridging study will usually require a high ascertainment rate of the clinical trial patient specimens for retesting. This ensures that the therapeutic effect observed with the CTA is also observed for the tobe-marketed companion diagnostic. In addition, the retested sample population should be representative of the intended-use population for the device, because reanalysis of the trial for the effectiveness of device can

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be biased if the sample population is not representative of the intent-to-screen or intent-to-diagnose population. To the extent possible, codevelopment sponsors should strive to retain all samples from the therapeutic registrational trial(s) and plan to assess available sample representativeness as part of the bridging study analysis plan. In cases where a proportion of samples are not available for retesting, imputation of missing test results should be included in the sensitivity analysis plan in order to assess the robustness of the therapeutic effectiveness in the intended population. Importantly, the bridging study plan should include a prespecified statistical analysis plan to account for assay discordance, missing samples, spectrum bias and covariates on drug efficacy. Investigational use In light of the interdependence between a companion diagnostic and its corresponding therapeutic product, the device (or a prototype of the device) will often have been used to select patients for a clinical investigation. The device in this setting is almost always considered to be investigational, because its performance characteristics in the intended use population will not be known. When a device is used in an investigational setting, sponsors should ideally plan to make use of a single test design and have a carefully defined standard operating procedure or protocol that is followed at each testing site. The standard operating procedure should include preanalytical steps and instructions for use to perform the assay. There should also be provisions that any protocol deviations are carefully recorded. Prior to use of the test in a clinical trial, the investigational device should be adequately analytically validated in order to ensure the safety of the device, to protect trial subjects and to support the robust interpretation of trial results. Clinical trials involving the use of investigational devices are required to comply with the IDE regulations, which may include the submission and approval of an IDE application prior to the initiation of the trial [22] . The IDE regulation, as described in 21 CFR 812, stipulates that the level of risk to the trial subjects dictates the level of regulatory control for a device used in a clinical investigation. Risk assessment for use of a device in therapeutic clinical trials is linked to the test performance in the context of the therapeutic safety profile, as well as the availability of alternative effective treatments. In addition, invasive sampling procedures used in the trial, specifically for the purpose of testing, are evaluated in order to assess the potential risk presented to the patients. A significant risk (SR) investigational device could potentially pose serious risk to subjects, whereas a nonsignificant risk (NSR)

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device should not present such risks. When an investigational device to be used in a therapeutic clinical trial is determined to be a SR, evidence demonstrating that the device is sufficiently analytically robust (e.g., accurate, stable and having adequate performance around the test’s clinical decision point[s]) should be provided for FDA review in an IDE application, among other elements, prior to use of the device in the therapeutic trial. In cases where a NSR investigational device is used in a therapeutic clinical evaluation, the study is subject to abbreviated IDE requirements under 21 CFR 812.2 (b) and an IDE application is not needed, although other requirements still apply. In other cases, studies may be exempt from the requirements of the IDE regulation, as described in 21 CFR 812.2 (c). If the investigational device is determined to be a SR or a NSR, the same types of validation studies should be performed prior to use of the device in the therapeutic product trial, even though the FDA will not review the data for a NSR study. The level of analytical validation is expected to be adequate enough to ensure that the device’s performance characteristics are sufficiently controlled in order to ensure that the device is safe and commensurate with the importance of the investigational device results in interpreting the clinical trial data. Conclusion & future perspective Since the approval of the HercepTest in 1998, significant strides have been made to establish a regulatory structure for companion diagnostic devices in the US. Test results obtained from companion diagnostics are used to guide treatment and clinical care decisions. Incorrect test results could prevent patients from receiving appropriate treatment, or even lead to patients receiving a harmful treatment. For example, an EGFR antagonist is indicated for colorectal cancer patients with wild-type KRAS, but not for colorectal cancer patients with KRAS-mutated tumors, because the latter have been shown to have increased tumor progression or increased mortality [23,24] . In this case, if a KRAS-mutant patient were detected as being wildtype for KRAS, then they may receive a harmful treatment. This highlights the importance of proper assay performance in terms of obtaining reliable results, supporting the need for the regulatory oversight of these types of medical devices in order to ensure their safety and effectiveness. Elements of the regulatory process that have been critical for the success of several codevelopment programs are the early planning and coordination of the respective product submissions and communication between the regulatory authorities and the external stakeholders, as well as communication within each group.

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Under the current model, at least one test for each therapeutic–biomarker combination is required. All of the FDA-approved molecular-based companion diagnostic devices are single-target tests, which collectively cover only a handful of molecular targets. In this context, ‘single target’ refers to an individual analyte or an individual gene. Several of these tests are multiplex tests that evaluate a number of different mutations in the same gene. Based on the current arsenal of approved DNA-based companion diagnostics, laboratories might need to perform multiple single-target tests for certain types of disease in order to determine the status of a set of biomarkers that are useful for making therapeutic choices. For example, there are different biomarkerdriven therapies approved for the treatment of metastatic non-small-cell lung cancer patients. To determine which treatment may benefit the patients, they would need to be screened for each of the biomarkers (e.g., mutations in EGFR and ALK ). This approach can be infeasible when there is limited availability of clinical specimens, and may increase time considerations for testing. Thus, the regulatory framework for companion diagnostics will likely need to be further developed in order to accommodate the challenges associated with assays based on ­high-throughput, multitarget ­techniques. There are several indications that biomarker testing will more frequently require the evaluation of multiple genetic or molecular targets. First, the list of clinically relevant biomarkers is expanding and the connections and common pathway interactions between different disease conditions are being investigated [25] . Second, high-throughput technologies are well poised to develop a single test that can interrogate a panel of genes or molecular targets, and as such, are increasingly utilized in practice for the clinical management of patients [26,27] . Third, the clinical trial design paradigm is shifting to test an array of biomarker-targeted therapies regardless of cancer site (umbrella trials) or different cancer types with a particular molecular alteration (basket trials) within a single trial [28] . Fourth, combination treatments consisting of different targeted therapies are being investigated for their synergistic effects [29] . As biomarkerdriven approaches are becoming increasingly employed in clinical trials and drug development, advances in high-throughput technologies and diagnostic designs will require additional regulatory considerations. Steps towards creating a regulatory pathway for in vitro diagnostics based on high-throughput sequencing technologies have been taken with the recent marketing authorizations of a next-generation sequencing analyzer and reagents [30–33] . From these examples, certain general approaches for analytical validation of the device have been defined, such as testing a com-

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Review  Lee & Shen prehensive set of representative variants in lieu of all possible variants and identifying appropriate reference methods and materials for accuracy testing. However, the cleared devices are not at this time indicated for use as companion diagnostics. There will be additional issues related to clinical validity, overlapping applications with previously approved companion diagnostics and validation for multiple indications, among others, which will need to be considered in the future.

Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.

Executive summary Background • Information regarding the genetic and molecular mechanisms underlying disease processes is being harnessed in order to develop targeted therapies, resulting in the personalization of medicine. • Companion diagnostic devices guide patient treatment decisions through the identification of biomarkerdefined populations. • Significant strides in personalized medicine have been made in the field of oncology.

Regulatory model for companion diagnostics • In 2014, the US FDA issued a final guidance document outlining the regulatory pathway for in vitro companion diagnostic devices. • Regulatory oversight for companion diagnostics is necessitated by the critical role that companion devices play in order to ensure the safe and effective use of a corresponding therapeutic product. • The current framework for the regulation of companion diagnostics stipulates that a diagnostic test is required when its use is essential for the safe and effective use of a therapeutic product, and approval of premarket submissions for a companion diagnostic and a corresponding therapeutic product should occur contemporaneously.

Codevelopment strategies • The FDA has developed efficient mechanisms to facilitate the regulatory review process for companion diagnostic devices. • To date, 18 companion diagnostics for oncology indications have received marketing authorization in the US. • Communication within the FDA and between codevelopment product sponsors is a key element to successful codevelopment programs, as is communication between the FDA and codevelopment product sponsors. • The development plan for a companion diagnostic should consider several regulatory aspects, including the device validation plans and premarket submission strategies for the codeveloped therapeutic product and for the diagnostic device.

Future perspective • Approaches to the regulation of companion diagnostics may need to address new challenges that arise from advancements in technology and the adoption of new clinical trial designs that are being employed in order to accelerate the development of personalized treatments.

References

5

Lesko LJ, Salerno RA. Pharmacogenomics in drug development and regulatory decision-making: the Genomic Data Submission (GDS) proposal, Pharmacogenomics 5(1), 25–30 (2004).

6

Lesko LJ, Salerno RA, Spear BB et al. Pharmacogenetics and pharmacogenomics in drug development and regulatory decision making: report of the first FDA–PWG–PhRMA– DruSafe workshop, J. Clin. Parmacol. 43(4), 342–358 (2003).

7

US FDA. Drug–Diagnostic Co-Development Concept Paper (2005). www.fda.gov

8

US FDA. List of Cleared or Approved Companion Diagnostic Devices (In Vitro and Imaging Tools). www.fda.gov/companiondiagnostics  



Provides a complete and current listing of all FDA-cleared or -approved companion diagnostics.

Papers of special note have been highlighted as: • of interest; •• of considerable interest 1

74

US FDA. Paving the Way for Personalized Medicine. www.fda.gov

2

US FDA. Guidance for Industry and Food and Drug Administration Staff – Companion Diagnostic Devices (2014). www.fda.gov 

••

Outlines US FDA policy and regulatory approval requirements for in vitro companion diagnostic devices.

3

US FDA. Drugs@FDA – FDA Approved Drug Products. www.accessdata.fda.gov

4

US FDA. Premarket Approval (PMA) – Dako HercepTest. www.accessdata.fda.gov

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9

US FDA. Classify Your Medical Device. www.fda.gov  10 11



US FDA. Regulatory Controls. www.fda.gov  US FDA. Federal Food, Drug, and Cosmetic Act (FD&C Act). www.fda.gov   Statutory requirements for food, drugs, medical devices and cosmetics are described in the Food, Drug, and Cosmetic Act.

12

US FDA. De Novo Classification Request for Ferriscan R2MRI Analysis System Decision Summary. www.accessdata.fda.gov/cdrh_docs/reviews/K124065.pdf 

13

US FDA. Part 892 Subpart B-Diagnostic Devices. www.gpo.gov

14

US FDA. Types of Applications. www.fda.gov 

15

US FDA. Fast Track, Breakthrough Therapy, Accelerated Approval and Priority Review. http://www.fda.gov

16

US FDA. Guidance for Industry and Food and Drug Administration Staff – Requests for Feedback on Medical Device Submissions: The Pre-Submission Program and Meetings with Food and Drug Administration Staff (2014). www.fda.gov

17

US FDA. Medical Device User Fee Amendments 2012 (MDUFA III). www.fda.gov

18

Code of Federal Regulations, Part 814 – Premarket Approval of Medical Devices. www.accessdata.fda.gov 

19

US FDA. Guidance for Industry and FDA Staff – Premarket Approval Application Modular Review. www.fda.gov

20

Code of Federal Regulations, Part 820 – Quality System Regulation. www.accessdata.fda.gov 

21

US FDA. Bioresearch Monitoring Program (BIMO). www.fda.gov 

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22

Code of Federal Regulations, Part 812 – Investigational Device Exemptions. www.accessdata.fda.gov 

23

US FDA. Labeling Information for Vectibix (Panitumumab). www.accessdata.fda.gov

24

Douillard JY, Siena S, Cassidy J et al. Final results from PRIME: randomized Phase III study of panitumumab with FOLFOX4 for first-line treatment of metastatic colorectal cancer. Ann. Oncol. 25(7), 1346–1355 (2014).

25

MacArthur DG, Manolio TA, Dimmock DP et al. Guidelines for investigating causality of sequence variants in human disease. Nature 508(7497), 469–476 (2014).

26

Biesecker LG, Green RC. Diagnostic clinical genome and exome sequencing. N. Engl. J. Med. 370(25), 2418–2425 (2014).

27

Wiita AP, Schrijver I. Clinical application of high throughput molecular screening techniques for pharmacogenomics. Pharmgenomics Pers. Med. 4, 109–121 (2011).

28

American Association for Cancer Research. Molecularly Informed Clinical Trials (2013). http://cancerprogressreport.org

29

Woodcock J, Griffin JP, Behrman RE. Development of novel combination therapies, N. Engl. J. Med. 364, 985–987 (2011).

30

US FDA. 510(k) Substantial Equivalence Determination Decision Summary (k132750). www.accessdata.fda.gov/cdrh_docs/reviews/K132750.pdf

31

US FDA. Evaluation of Automatic Class III Designation for MiSeqDx Platform Decision Summary (k123989). www.accessdata.fda.gov/cdrh_docs/reviews/K123989.pdf

32

US FDA. Evaluation of Automatic Class III Designation for MqSeqDx Universal Kit 1.0 Decision Summary (k133136). www.accessdata.fda.gov/cdrh_docs/reviews/K133136.pdf

33

US FDA. 510(k) Substantial Equivalence Determination Decision Summary (k124006). www.accessdata.fda.gov/cdrh_docs/reviews/K124006.pdf

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Regulatory considerations for companion diagnostic devices.

The emergence of companion diagnostic devices has been spurred by drug discovery and development efforts towards targeted therapies, particularly in o...
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