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Companion diagnostics: a regulatory perspective from the last 5 years of molecular companion diagnostic approvals Expert Rev. Mol. Diagn. 15(7), 869–880 (2015)

Donna M Roscoe, Yun-Fu Hu and Reena Philip* Division of Molecular Genetics and Pathology, Office of In Vitro Diagnostics and Radiological Health (OIR), CDRH, US FDA, 10903 New Hampshire Ave, Silver Spring, MD 20993-0002, USA *Author for correspondence: [email protected]

Companion diagnostics are essential for the safe and effective use of the corresponding therapeutic products. The US FDA has approved a number of companion diagnostics used to select cancer patients for treatment with contemporaneously approved novel therapeutics. The processes of co-development and co-approval of a therapeutic product and its companion diagnostic have been a learning experience that continues to evolve. Using several companion diagnostics as examples, this article describes the challenges associated with the scientific, clinical and regulatory hurdles faced by FDA and industry alike. Taken together, this discussion is intended to assist manufacturers toward a successful companion diagnostics development plan. KEYWORDS: approval . cancer . companion diagnostics . FDA . personalized medicine

Fundamental to the development of effective therapeutic products for a disease, is the understanding of the biological process driving the disease. Advances in molecular technology have allowed the genetic mechanisms underlying the causes of disease and disease progression, as well as other genetic biomarkers that help to segregate disease into prognostic subgroups, to be identified and pursued as targets for therapeutic product development. Approximately one in five original novel drugs approved by the US FDA since 2010 is considered a ‘targeted’ therapy [1]. This therapeutic product design approach is the culmination of years of clinical observation and scientific and technological progress, and is referred to as ‘personalized medicine’ [2]. In the 21st century, personalized medicine is the realization that for every disease, there are molecular differences between patients and that these differences can be used to optimize medical treatment decisions [3]. In order for these differences to be clinically useful, they must be detectable in a reliable and reproducible manner. The co-development of therapeutic products informahealthcare.com

10.1586/14737159.2015.1045490

and their associated molecular markers, therefore, relies on analytically valid diagnostic tests. Diagnostic tests that are essential to the safe and efficacious use of a therapeutic product are called ‘companion diagnostics’ [4]. FDA regulatory framework for companion diagnostics

In vitro diagnostic tests (IVDs) are medical devices subject to FDA regulation [21 CFR§ 809.3] [5]. The FDA regulates medical devices based on how the test is used (e.g., specimen type, methodology), which is the test intended use; what disease condition the test is used for and why the test is used (i.e., the tests’ indications for use) and the risks to the patients that could occur if the test fails. In July 2011, FDA released a draft guidance outlining the policy regarding regulation of companion diagnostics and the corresponding targeted therapeutic. The guidance became final on 6 August 2014 [4]. This guidance outlined definitions, expectations for contemporaneous approval of the device with the therapeutic product and labeling factors.


2015 Informa UK Ltd

ISSN 1473-7159

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Since companion diagnostics are used to make specific treatment decisions, an incorrect result could lead to inappropriate patient management. For therapeutic products with demonstrated efficacy, a false-positive companion diagnostic result could lead to use of a therapy for which the patient may not benefit, a delay in receiving an available alternative effective treatment and potentially toxic side effects of the therapeutic product not intended for them. Similarly, a false-negative result could prevent the patient from receiving a therapy from which they might benefit. For this reason, companion diagnostics take on the risk profile of the therapeutic decision being made and are therefore generally considered high risk (i.e., class III) and require the device manufacturer to submit a regulatory dossier for the highest level of review in a premarket application to obtain FDA approval. To date, one companion diagnostic (the Ferriscan R2-MRI Analysis System; Resonance Health Analysis Services Pty., LTD) has been considered to pose moderate risk to patients (i.e., class II). A list of approved companion diagnostics is available at the FDA website [6]. The FDA approves a medical device based on its determination of the safety and effectiveness of the device. The device manufacturer (or sponsor of the premarket submission) should provide the FDA with a reasonable assurance that the probable benefits of using the device outweigh any probable risks [860.7 (d)(1)] and a reasonable assurance that the use of the device will provide clinically significant results [860.7(e)(1)]. This evidence is determined for diagnostic tests by assessing the analytical validation (assurance of test performance) and clinical validation (correlation between test result and clinical condition). The strongest scientific evidence in support of the safety and effectiveness of a companion diagnostic consists principally of well-controlled investigations of the corresponding therapeutic product, in which the analytically validated companion diagnostic intended for commercialization is the device used to screen and enroll patients in the clinical trials. In this case, the clinical performance and clinical significance of the companion diagnostic device is established using data from the clinical development program of the corresponding therapeutic product in the intended-to-treat population. More extensive information on FDA regulation of medical devices and analytical validation for IVDs is described elsewhere [7–10]. Types of companion diagnostics

Companion diagnostics detect specific biomarkers that are linked to therapeutic benefit, either as targets of the therapeutic mode of action, or as factors that impact the course of the disease for which the therapeutic may have the largest treatment effect. Companion diagnostics are largely designed to: identify patients who are most likely to benefit from the therapeutic product, or for whom knowledge of safety and efficacy of the therapeutic product is available due to the design of the clinical trial; identify patients likely to be at increased risk for serious adverse reactions as a result of treatment with the therapeutic product or monitor response to treatment with the therapeutic product for the purpose of adjusting treatment (e.g., discontinuation) to achieve expected safety or effectiveness [4]. 870

Since 2010, the FDA has approved a number of companion diagnostics used to select cancer patients for whom there were few therapeutic options as candidates for treatment with contemporaneously approved novel therapeutics (TABLE 1). These approvals involved significant interagency collaboration and were supported by successful pharmaceutical and diagnostic manufacturer collaboration such that the companion diagnostic approvals occurred on the same day as the therapeutic product approvals. Links to the summary of safety and effectiveness are available from the FDA companion diagnostic weblink [11]. Lessons learned

Companion diagnostics are illustrative of the spirit of personalized medicine in that each device reviewed to date has its own unique challenges, scientific, regulatory or otherwise, requiring case-by-case consideration of the best path forward. The challenges include but are by no means limited to: managing trial design considerations to support investigational device use alongside investigational therapeutic product development (which follow different laws, regulatory policies and trajectories); managing sources of bias that can affect device validation, such as laboratory pre-screening and selection of specimen types and planning ahead for the needs of device validation with respect to sample banking, annotation and appropriate statistical analyses in the event a ‘bridging study’ is needed to demonstrate clinical concordance between a prototype version and a final version of the companion diagnostic test. Many clinical enrollment strategies can lead to downstream challenges for which a better approach may lead to more streamlined review (TABLE 2). Here, we discuss highlights of the unique considerations and lessons learned for many of the companion diagnostics that came under FDA review in recent years. Using a single, analytically reliable companion diagnostic test is preferred for enrollment into investigational therapeutic product trials

The pharmaceutical sponsor is responsible for defining the target population for the safe and effective use of the therapeutic product, and ensuring this same population can be identified when the therapeutic product is on the market [12]. The safety and efficacy of the therapeutic product are assessed in the enrolled population, and not evaluated in excluded patients, including those excluded by a test. Therefore, when a clinical trial uses a specific test to define the population, it is important to recognize that the selection of the patients is based on that specific test and the variables by which the analytical performance parameters characterize the specimen tested. This may include, but is not limited to, the biomarker(s) (e.g., genotypes, isoforms) it detects, and the analytical sensitivity and analytical specificity based on the test cut-off or clinical decision point(s) used to segregate the patients into the various subgroups (e.g., biomarker positive and negative). When multiple different tests are used, discordance between tests can lead to uncertainty about patient selection. In particular, whether the safety and Expert Rev. Mol. Diagn. 15(7), (2015)

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Table 1. FDA same-day co-approvals of therapeutic and molecular companion diagnostics in the last 5 years. Date

Therapeutic

Companion diagnostics

Therapeutic indication‡

2010-October

Herceptin† (trastuzumab)

Dako HercepTest and HER2 FISH pharmDx Kits†

– HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma (Under Warnings and Precautions: HER2 Testing should be performed using FDA-approved tests by laboratories with demonstrated proficiency)

2011-August

Zelboraf (vemurafenib)

Roche cobas 4800 BRAF V600 Mutation Test

– Unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test

2011-August

Xalkori (crizotinib)

Vysis ALK Break Apart FISH Probe Kit

– Locally advanced or metastatic NSCLC that is ALK-positive as detected by an FDA-approved test

2012-July

Erbitux (cetuximab)

QIAGEN therascreen KRAS RGQ PCR Kit

– K-Ras mutation-negative (wild-type), EGFR-expressing, metastatic colorectal cancer as determined by FDA-approved tests

2013-February

Kadcyla (ado-trastuzumab emtansine)§

Dako HercepTest and HER2 FISH pharmDx Kits

– HER2-positive metastatic breast cancer (Under Warnings and Precautions: Her2 Testing: Perform using FDA-approved tests by laboratories with demonstrated proficiency)

2013-May

Tafinlar (dabrafenib)

bioMerieux ThxID BRAF Assay

– Unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test

2013-May

Mekinist (trametinib)

bioMerieux ThxID BRAF Assay

– Unresectable or metastatic melanoma with BRAF V600E or V600K mutations as detected by an FDA-approved test

2013-May

Tarceva (erlotinib)

Roche cobas EGFR Mutation Test

– Locally advanced or metastatic NSCLC with EGFR mutation as determined by FDA-approved tests

2013-July

Gilotrif (afatinib)

QIAGEN therascreen EGFR RGQ PCR Kit

– Locally advanced or metastatic NSCLC with EGFR mutation as determined by FDA-approved tests

2013-September

Perjeta (pertuzumab)§

Dako HercepTest and HER2 FISH pharmDx Kits

– Treatment of patients with HER2-positive metastatic breast cancer (Under Warnings and Precautions: Her2 Testing: Perform using FDA-approved tests by laboratories with demonstrated proficiency)

2014-May

Vectibix (panitumumab)

QIAGEN therascreen KRAS RGQ PCR Kit

– K-Ras mutation-negative (wild-type), EGFR-expressing, metastatic colorectal cancer as determined by FDA-approved tests

2014-December

Lynparza (olaparib)

Myriad BRACAnalysis CDx

– Patients with deleterious or suspected deleterious germline BRCA mutated (as detected by an FDA-approved test) advanced ovarian cancer

†

Co-approval for new indication. Only a portion of the therapeutic indication is presented as it relates to the test. For complete information about the therapeutic indication refer to Drugs@FDA available at [42]. § Same day approvals of drug-device combinations for which the device was already approved for the target population in conjunction with herceptin. ALK: Anaplastic lymphoma kinase; NSCLC: Non-small-cell lung cancer. ‡

efficacy observed in the patients enrolled would be similarly observed in a post-approval setting. The issue of whether a therapeutic product population was identified prior to the onset of a clinical trial was the topic of the 22 March 2010, the FDAs Oncologic Drugs Advisory Committee (ODAC), which convened to discuss the approval of the therapeutic with proposed trade name Omapro (omacetaxine mepesuccinate; ChemGenex Pharmaceuticals). The therapeutic product indication was for the treatment of adults with chronic myeloid leukemia who failed prior therapy with the drug imatinib (Gleevac; Novartis) and whose leukemic cells contain the genetic alteration known as the BCR-ABL T315I mutation. The informahealthcare.com

sponsor used two different assays at the two central laboratories for the confirmation of T315I mutation status prior to patient enrollment. However, the comparability of these tests was unknown, and 23 of the 66 patients (including 5 of 11 responders) did not have central laboratory confirmation of the mutation at enrollment at either site. The panel members (7 out 8) voted that ‘a well characterized in vitro diagnostic to identify patients with the T315I mutation be required and reviewed by the FDA and correlated to clinical trial results prior to approval of omacetaxine for the proposed indication’ [13]. Industry took notice of the need to appropriately control the patient selection method in the protocols, and assuring that the 871

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Table 2. Common challenges in the companion diagnostic FDA review and approval process. Common pitfalls

Challenges to the FDA review process

Preferred approach

Use of multiple tests to test patients specimens to select for trial

– Test results obtained from a variety of laboratory-developed tests for which the concordance between testing methods is not known, risks ambiguity in defining the intentionto-treat population, with uncertainty for generalizing the trial results to post-approval use of the drug – Missing samples for bridging studies – Prescreening (or double screening) may lead to bias in patient and specimen set because patients with tumors that express low levels of analyte or whose tumors are at the cutoff (i.e., analytically challenging test specimens) are eliminated from the trial

Either employ one test/method, using the same analytically validated reagents and procedure for testing and result reporting, at all testing sites, or have all patients screened by a single, analytically validated test at a central laboratory

Lack of analytical validation prior to use in trial, or inappropriate specimen types used to validate the assay

– Undetected issues show up in clinical trial population – Poor reproducibility leads to high discordance in bridging studies – Samples/patients not reflective of target population

– Develop classifier and/or cutoffs using samples from target population – Thorough analytical validation with sufficient number and representation of clinical specimens to detect sources of analytical variability, or use of the test intended for coapproval to select patients for trial

Targeted trials allows for assessment of drug efficacy in only one subset defined by test

– Information about drug efficacy in the allcomers set results in lack of information about whether the test clinical decision point (cutoff) is optimized or clinically valid – No information about the clinical sensitivity or clinical specificity in terms of ability to identify patients who will benefit from those who will not benefit When drug efficacy is studies in one subset, there isn’t any outcome data in the other subset should a bridging study be needed due to changes in device design

Stratify patients in trial according to test results, or make use of Phase II trial data, adaptive trial designs and other trial designs to obtain information

Missing samples; instability of analytes during storage

Bridging studies require retesting specimens with the market-ready test kit. Missing samples, or unevaluable samples means missing data in the bridging analysis

Ideally, finalize the specimen and pre-analytic procedures so that stable analyte can be stored for retesting without concern for those variables Plan ahead with a specimen banking strategy, evaluate impact of storage on specimen

Retrospective assignment of cutoffs in pivotal trial

Retrospective analysis might result in treatment assignments that are unbalanced with regard to the biomarker status, and will lead to difficulty in examining the association between biomarker and response to therapeutic

Stratify treatment groups according to biomarker status and test clinical decision points

Mid-Trial Design Changes

Changing the cutoff, measuring range or any test parameter that could change the results for a patient sample, potentially changes who is enrolled

If trial design changes are anticipated, pre-specify a successful bridging study

Use of RUO instruments and reagents

FDA cannot clear or approve reagents and instruments labeled for research use only for IVD use

Ensure appropriate labeling of all IVD components consistent with regulation to avoid having to re-design the assay

IVD: In vitro diagnostic test.

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Lessons learned in companion diagnostics

patients in the trial have the disease or condition being studied. The need for adequate and well controlled clinical trial(s) for FDA drug approval when patients selection is required on the basis of biomarker measurement or detection, dictates the need to ensure that biomarker detection is based on a single, reliable test method. The co-development process plans for the availability of a companion diagnostic to identify therapeutic candidates expected to benefit from the drug consistent with the population enrolled in the trial in the post-approval setting. Lesson learned: The test design and protocol should be locked down and a companion diagnostic testing strategy should be implemented for contemporaneous approval of therapeutic products and the companion diagnostics. Assay design can affect trial enrollment

As previously stated, pharmaceutical and diagnostic partners should be fully aware of how the assay design establishes the performance parameters of the test used to select patients. Analytical validation of a test prior to its use in the trial can reveal what may lead to the unintentional inclusion or exclusion of patients in the intended target population. Perhaps the most common case is observed when the detection method cross-reacts with other biomarkers that are not the biomarkers of interest. Cross-reactivity is observed with specific antibodies in immunohistochemistry (IHC) assays or with genetic markers. BRAF is an example of the latter. BRAF is a signal transduction protein kinase. The mutated form of the protein is the target of several therapeutic development programs because it has increased kinase activity believed to be responsible for driving cancer growth. On August 2011, vemurafenib (Zelboraf, Hoffmann-LaRoche) was approved by FDA for the treatment of patients with unresectable or metastatic melanoma with the BRAF V600E mutation as detected by an FDA-approved test [14]. The vemurafenib approval occurred concurrently with the FDA approval of the cobas 4800 BRAF V600 Mutation Test (Roche Molecular Systems, Inc. [RMS]), which is a real-time PCR-based IVD designed to detect the V600E BRAF allele using DNA extracted from formalin-fixed paraffin embedded (FFPE) human melanoma tissue. Since vemurafenib was designed specifically to target the V600E mutant BRAF protein, the RMS assay was successfully validated to detect the V600E mutation. However, what was apparent at the conclusion of the vemurafenib trial was that the test displayed limited cross-reactivity to V600K, resulting in the enrollment of some V600K patients (estimated at approximately 5% of the enrolled population). Some treatment effect was observed in the V600K population and HoffmanLaRoche continued to study the effect in this population [14,15]. Overall, although the test displayed this unintended crossreactivity, it was successful as a companion diagnostic for vemurafenib because Hoffmann LaRoche and RMS had committed to a successful codevelopment path: the test intended for marketing was the test used in the strongly positive therapeutic product clinical trial, and all patient specimens that were informahealthcare.com

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tested to determine patient eligibility were screened using the RMS test intended for marketing [14–18]. Therefore, the treatment effect in the population – as selected by the test – was known. Had it been necessary to ‘bridge’ the clinical trial assay (CTA) to a new version of the test that did not detect the V600K variant, a bridging study would have had to account for these specimens. Analytical validation is a necessary prerequisite to understanding the performance of the diagnostic and its potential impact on trial enrollment. Lesson learned: Issues such as cross-reactivity may select a population for which the drug may not be intended. Enrolling both test-positive & test-negative cases allows for assessment of the clinical significance of the test

Having identified markers that may be functionally relevant to the disease for which the therapeutic is intended to benefit, sponsors may decide to conduct clinical trials only in one marker subset of the disease group. Understandably, this is the case when the therapeutic has been specifically designed to target the marker, but it could be the case when the marker is believed to have an association with response based on retrospective exploratory research in patient specimens from prior clinical trials, or when the marker is believed to identify a subset of patients believed to have a different prognostic outcome and therefore a larger therapeutic effect is anticipated. However, in the absence of outcome data in the entire population, information about the relevance of the marker to the therapeutic benefit in the pivotal clinical trial is not available, and there is no information to indicate that the clinical decision point (i.e., the test cutoff) is the optimal one. One well-known example of the necessity of appropriately assessing a clinical decision point is the estrogen receptor (ER) IHC assay for breast cancer and its use as a marker for selecting patients for endocrine therapies [19]. The lack of a clear understanding of clinical benefit around clinical cutoffs, as well as differences in test performance around clinical cutoffs, made it difficult to gain consensus on a ‘universal cutoff’ associated with treatment as it relates to ER testing. The guidelines were updated to reflect the need for a robust assay and the desire to not withhold treatments that may be beneficial in a larger group of women given the therapeutic safety profile [20]. Similarly, questions were raised in the case of anaplastic lymphoma kinase (ALK) companion diagnostic. The ALK tyrosine kinase receptor or CD246 (cluster of differentiation 246), is associated with oncogenic activity due to chromosomal rearrangement of the ALK gene leading to the formation of fusion products with any of several other genes, and by DNA mutations within the gene itself. A fusion gene product consisting of parts of the echinoderm microtubule-associated protein-like 4 (EML4) gene and the ALK gene (EML4–ALK fusion gene) results in the expression of a cytoplasmic chimeric protein with constitutive kinase activity and is a key driver of oncogenesis in a subset of patients with non-small-cell lung cancer (NSCLC) [21]. The frequency of EML4–ALK ranges from 1.5 to 6.7% of patients with NSCLC, making for a very small set of eligible patients for an 873

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EML4–ALK fusion targeted therapy. In August 2011, crizotinib (Xalkori; Pfizer Inc.) was approved based on the results from an ongoing Phase II, multicenter, multinational, open-label, singlearm study evaluating its safety and efficacy in patients with advanced NSCLC harboring a translocation or inversion involving the ALK gene locus as determined by the Vysis ALK Break Apart FISH assay used for enrollment [22,23]. The Vysis ALK Break Apart FISH Probe Kit from Abbott Molecular, Inc. is a qualitative test to detect rearrangements involving the ALK gene via FISH in FFPE NSCLC tissue specimens and was simultaneously approved with crizotinib as an aid in identifying patients eligible for treatment. While safety and efficacy of crizotinib was assessed in patients with ALK-positive advanced NSCLC, data were also available for an additional 23 patients with locally advanced or metastatic ALK-negative NSCLC, by the Vysis ALK Break Apart FISH Probe Kit. The initial estimate of the response rate in this population was demonstrated to be similar to that in patients with ALK-positive NSCLC. Despite a very small number of patients, results from this study suggested that crizotinib could potentially provide benefits to a substantial number of patients with NSCLC not limited to the ALK fusion protein. As a result, the study of patients with ALK-negative NSCLC became a post-marketing commitment for crizotinib [22,23]. Another example highlighting the significance of noting therapeutic efficacy for both test-defined subgroups is ipilumumab (Yervoy; BristolMeyersSquibb), which was approved for patients with advanced melanoma in March 2011. Ipilumumab is a cytotoxic T-lymphocyte antigen 4 inhibitor whose mechanism of action is intended to increase T-cell immune activity [24,25]. All patients in the clinical trial were selected on the basis of having the HLA-A2*0201 genotype because patients in the control arm were treated with a HLA-A2*0201-restricted peptide derived from the melanocyte differentiation antigen, gp100. Although the ipilumumab effect was not believed to be associated with this particular marker, the need for a companion diagnostic was dependent on whether the sponsor could demonstrate that the survival benefit was not limited to HLA-A2*0201-positive melanoma patients because safety and efficacy was only evaluated in the HLA-A2*0201 population. Because additional trials enrolled and treated without respect to HLA-A2*0201, the sponsor was able to conduct retrospective analyses of the efficacy in other trials where the population was not restricted. The results demonstrated that ipilumumab efficacy was independent of the haplotype [24,25] and FDA accepted these data in support of an unrestricted population claim. Lesson learned: There can be significant benefit to studying at least a small population of markernegative patients. Therapeutic & device claims can be limited due to mutations lacking analytical or clinical validation

As described above, the test is designed and analytically validated to detect the markers in specimens from patients for whom the therapeutic product is indicated. Many therapeutic products are intended to treat patients with one of many possible mutations and hence companion diagnostics with the 874

ability to detect the potential spectrum of markers are designed and planned. During the review and approval process of the therapeutic product and associated companion diagnostic, challenges arise when validation is lacking for any of several reasons. This was the case with the recent approvals of EGFR mutations tests. Mutations in the EGFR (also sometimes called ERBB or HER1) gene located in the tyrosine kinase domain of the EGFR protein can cause abnormal receptor signaling, and a number of tyrosine kinase inhibitors have been developed to target the EGFR tyrosine kinase domain. The FDA approved two such drugs in 2013 for the initial treatment of NSCLC patients with specific EGFR mutations (i.e., exon 19 deletions and exon 21 L858R substitution mutations) as determined by the concurrently approved companion diagnostics (TABLE 3). The cobas EGFR Mutation Test was approved for selection of NSCLC patients for first-line treatment with erlotinib (Tarceva; Genentech and Astellas Pharma Inc.) [26]. Similarly, the therascreen EGFR RGQ PCR Kit (QIAGEN) was approved for selection of NSCLC patients for first-line treatment with afatinib (Gilotrif; Boehringer Ingelheim) [27]. To establish the clinical validity of the tests, banked samples from the clinical trials were retrospectively tested in a bridging study to the CTA used to screen patients for enrollment into the respective trials. There were several challenging issues to resolve: Can a companion diagnostic label include claims for mutations for which patients were not originally selected by the CTA in the original clinical trial? For a companion diagnostic designed to detect a pre-specified set of mutations, should the companion diagnostic label be able to include claims for mutations for which no single patient was observed in the trial? Is analytical validation necessary to support every claimed mutation? Under what conditions can a therapeutic product label include claims for mutations when the test screened for the mutations, but the mutation was not represented, or minimally represented in the clinical trial? In these two cases, the decision was that mutation claims for the therapeutic product and the IVD device must be pre-specified, observed in the trial and analytically validated. Additionally, to support clinical claims of any mutation detectable by the test, the mutation should be observed in a sufficient number of patients enrolled in the clinical study unless the mutation is part of a collective group of overlapping mutations (e.g., exon 19 deletion mutations). For the cobas EGFR Mutation Test, only exon 19 deletions and exon 21 L858R mutations were pre-specified in its clinical validation study; therefore, no clinical or analytical claim was granted for other EGFR mutations. In contrast, even though a number of other mutations (e.g., T790M, L861Q, G719X, S768I and Exon 20 Insertions) along with exon 19 deletions and exon 21 L858R mutations, were pre-specified and analytically validated using the prototype therascreen EGFR RGQ PCR Kit in its clinical validation study, while analytical claims were given, clinical claims were not granted for these ‘other’ mutations because of the small sample size for each mutation, Expert Rev. Mol. Diagn. 15(7), (2015)

Lessons learned in companion diagnostics

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Table 3. Review comparison of two companion diagnostics that test for EGFR activating mutations. cobas EGFR Mutation Test

therascreen EGFR RGQ PCR Kit

Therapeutic

Erlotinib (Tarceva)

Afatinib (Gilotrif)

CTA

Central laboratory using Sanger sequencing followed by confirmatory testing for exon 19 deletions (GeneScan) and exon 21 L858R mutations (TaqMan PCR)

Three laboratories using the QIAGEN EGFR mutation assay prototype

CTA mutations

Exon 19 deletions and exon 21 L858R substitution mutations

Exon 19 deletions, exon 21 L858R substitutions, T790M, L861Q, G719X, S768I and Exon 20 Insertions

CDx IVD mutations validated clinically and analytically

Exon 19 deletions (different representation from CTA) and exon 21 L858R substitution mutations

Exon 19 deletions and exon 21 L858R substitution mutations

Outcome assessment

PFS and response rates for all patients enrolled in the EURTAC trial (i.e., CTA-positive) were compared with the outcomes of patients whose specimens were mutation-positive upon retrospective testing with the cobas EGFR Mutation Test

PFS for all patients enrolled in the LUX-Lung 3 study (i.e., CTA-positive) were compared with the outcomes of patients whose specimens were mutation-positive upon retrospective testing with the therascreen EGFR RGQ PCR Kit

Notable

Eight (8) exon 19 deletions observed in the EURTAC trial can also be detected by the cobas EGFR Mutation Test; however, analytical performance of the cobas EGFR Mutation Test in detecting these mutations has not been evaluated. As a result, they are listed as crossactivity in the device labeling

The results demonstrated that patients whose tumors had exon 19 deletions and exon 21 L858R substitution mutations of the EGFR gene received treatment benefits with Gilotrif when compared with the control group. However, assessments of the clinical safety and efficacy of Gilotrif in NSCLC with other mutations (i.e., T790M, L861Q, G719A, S768I and 2 Exon 20 insertions) were inconclusive because each of them was only observed in a small number of NSCLC patients enrolled in the study, even though therascreen EGFR RGQ PCR Kit is analytically validated to detect these mutations

CTA: Clinical trial assay; IVD: In vitro diagnostic test.

and inconclusive efficacy associated with this group of ‘other’ mutations observed in the trial. With the ever-increasing number of actionable genetic alterations and multiplicity of the test comes the realization that it is neither practical to validate each analyte in a large panel nor possible to find enough samples to validate those rare mutations. Alternative approaches were accepted for FDA review and approval of these companion diagnostics, such as the use of FFPE cell lines for rare variants. Additionally, for the EGFR exon 19 mutations, representation of the more prevalent mutations and a few selected representative mutations was sufficient for most of the analytical studies. Lesson learned: The assay claims and therapeutic product claims are integrated. The similarities and differences in the two drug-companion diagnostic device co-approvals are noted in TABLE 2. Bridging studies should be pre-planned & pre-specified

FDA believes that logistically the simplest scenario is when the same diagnostic test that is planned for co-approval with the drug be used to determine patient eligibility for the drug in the clinical trial. However, CDRH recognizes that it is not always feasible or practical to have the final test version available at the time of the trial that will support therapeutic product registration. Companion diagnostic development and informahealthcare.com

development of the corresponding therapeutic product may have differing timelines. For example, a therapeutic product company may not be certain of the requirement for a companion diagnostic at the time the trial is initiated, and the pharmaceutical company may not want to commit the resources to the development of a companion diagnostic until the benefits of the companion diagnostic to identify target defined, pharmacologically relevant subsets of patients become evident in later stages of the drug development program. Business development agreements, product development issues and other logistical challenges may also drive non-aligned timelines. For these reasons, patient screening for a trial may use a single central reference method or an interim device prototype for a part or the entirety of the trial. Discordance between the trial version (i.e., CTA) and the final version of the test or platform with respect to patient enrollment may make clinical study results uninterpretable. In such cases, manufacturers should plan a bridging study between the CTA and final devices for all specimens screened (i.e., the ‘intent-to-diagnose’ population), not just those from enrolled patients, to demonstrate that the trial version (i.e., CTA) and final version of the test are concordant and that the therapeutic product safety and efficacy are preserved with the final (commercial) version of the test. In particular, the bridging study should demonstrate that 875

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the final device can support the established efficacy performance of the therapeutic product [28–30]. Lessons learned from reviewing co-development bridging studies suggest that manufacturers should consider the following if the final device is not used in the trial(s) that will support regulatory approval of the therapeutic product:

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.

.

.

. .

The samples used to design the test should not be used to validate the test, and therefore changes to the test should not be made based on pivotal trial results. Otherwise, information about the optimal patient selection threshold (e.g., cutoff or clinical decision point) obtained in the course of the clinical validation study with patient specimens, becomes data used to design the assay and is no longer considered ‘validated’. Every effort should be made to appropriately retain, annotate and store all clinical trial specimens (e.g., Phase II, Phase III, marker positive and negative) in order to be able to fully validate the version of the test that will be marketed. To the extent possible, all samples from the clinical trial should be retested with the final device. It may be necessary for the Informed Consent documentation to explain the additional use of the samples; sponsors should check with their institutional review board(s) to determine if any additional informed consent issues arise when samples are retained and used for bridging studies. The re-analysis of the trial data for effectiveness of the test should be pre-specified. The re-analysis of the trial data for the effectiveness of the final device may need to consider multiple sources of evidence, including the analysis of the effectiveness of the CTA. and the analytical concordance between the device and the CTA.

If only a subset of samples will be available for retesting, the validity of the bridging strategy rests on demonstrating that the samples available for retesting are representative of the population recruited and tested for enrollment into the therapeutic clinical trial. The samples available for the bridging study (i.e., evaluable subjects) should also be representative of the intended use population for the device. If the samples available for retesting are not representative, re-analysis of the trial for effectiveness of the device is potentially biased. To assess whether the samples available for retesting are representative of the intended use population, the sponsors of the companion diagnostic device submission should identify variables that could be foreseen to have effects on the test result or the clinical outcome. Sponsors should pre-specify a comparison of the retested and non-retested samples on the distribution of these variables, pre-specify an analysis of the robustness of device effectiveness to missing retest results, which may include imputation of missing test results assuming: they are missing at random or they are uninformative for the clinical outcome. It is worth nothing that many of the most important variables pertain to analytical and pre-analytical characteristics of the sample (such as tumor size, melanin content, proportion of necrotic tissue) 876

not characteristics of the subject (e.g., clinical and demographic variables). Bridging studies have been conducted when therapeutic efficacy was known for both the test-positive and test-negative cases (i.e., the ‘all comers’ set), and for marker-positive cases only. Below two examples are described. Retrospective testing & predictive biomarkers

The KRAS gene codes for GTP-binding protein that is a key signaling intermediate downstream of EGFR. KRAS mutations are found in approximately 30–50% of colorectal cancer (CRC) tumors and are common in other tumor types as well. Certain mutations in KRAS results in a constitutively activated protein, and it is believed that mutated KRAS may confer resistance to anti-EGFR monoclonal antibody therapies [31,32] and that response is limited to patients whose tumor is KRAS wild-type. In this context, ‘wild type’ refers only to the absence of specific mutations for which testing was done, for example, codons 12 and 13. Additional mutations not tested may have been present. Erbitux (cetuximab; Imclone/BristolMeyerSquibb/Lilly) was originally approved based on overall survival data demonstrating efficacy and safety data from the CA225-025 trial in patients with advanced colorectal cancer (CRC). However, to support a new indication in patients whose tumors do carry an activating KRAS mutation, Imclone (the manufacturer of Erbitux [cetuximab]), successfully petitioned the Agency to allow indications for use in only those patients whose tumors harbor the wild-type KRAS gene, in their primary efficacy analyses and in their drug labels. Following the 16 December 2008, ODAC meeting to discuss the use of evolving biomarker information and retrospective analysis to refine a biomarker population, FDA determined that prospectively collectedretrospective data could be used to support revised efficacy claims provided a certain criteria were satisfied. One of these criteria was the availability of an analytically validated test [33,34]. Imclone/BMS/Lilly partnered with QIAGEN to develop a companion diagnostic test for KRAS mutations [35]. In the prospective-retrospective study used to support the companion diagnostic approval, 79% of the patient samples were available for retesting with the QIAGEN therascreen KRAS RGQ PCR test [34]. Using the KRAS-evaluated population, the primary and secondary analyses of cetuximab efficacy on survival were stratified to evaluate the treatment benefit within the KRAS mutation-negative (wild type) and KRAS mutation-positive subsets as defined by the therascreen KRAS Kit. A statistical analysis plan accounted for the missing patient samples in which covariates of the missing samples including patient characteristics, disease characteristics and specimen characteristics were considered. In addition, the predictive effect of the KRAS mutation status on cetuximab efficacy (for both overall survival and progression-free survival [PFS]) was evaluated with a test for interaction between treatment group and KRAS mutation status. A statistically significant increase in overall survival was observed in the mutationExpert Rev. Mol. Diagn. 15(7), (2015)

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negative (wild-type) population, but was not observed in the KRAS mutation-positive group. However, a statistically significant predictive effect was not demonstrated between the two treatment groups, meaning that the test could select patients who were likely to benefit, but it could not claim to predict the effect. Since then, more research has suggested that KRAS, NRAS and BRAF wild-type status, in addition to KRAS wild-type status may improve benefit for EGFR monoclonal antibody treatments [36]. Bridging studies with marker-positive-only trials

Many trials are conducted in an enriched patient population, where only those patients with a specific biomarker status (e.g., test positive) are enrolled into a trial with an investigational therapeutic product. Trials typically use enriched populations when there is preliminary evidence to suggest that patients without the biomarker (e.g., test-negative) are not expected to benefit, or may experience an excess of adverse events. These studies are expected to be well-controlled studies with the test protocol locked down and a companion diagnostic testing strategy planned [37], however, it should be noted that such clinical validation strategies do not provide information about the significance of the biomarker or test cutoff as applied in trial, to therapeutic product response (i.e., generate no information about whether the biomarker is predictive for response) [38]. When pharmaceutical manufacturers use tests to select a clinical trial that is limited to a marker-defined subgroup, the companion diagnostic indication is limited to a patient ‘selection’ claim. On 29 May 2013, the two therapeutic products dabrafenib (Tafinlar; GlaxoSmithKline) and trametinib (Mekinist; GlaxoSmithKline) were approved for treating metastatic melanoma patients whose tumors are positive for the BRAF V600E (for Tafinlar), and BRAF V600E and V600K mutations (for Mekinist). At the same time, the bioMerieux THxID BRAF Kit was approved as a companion diagnostic device intended for the qualitative detection of the BRAF V600E and V600K mutations in DNA samples extracted from FFPE human melanoma tissue [39]. In the therapeutic product trials, a central testing laboratory was used to test patient specimens with a CTA. Bridging to the ‘to-be-marketed test’ was thus necessary: this was the first case where a bridging study was needed for a marker–positive-only trial. For clinical validation, specimens from patients were banked and retested in retrospective studies designed to establish the analytical and clinical concordance between the THxID -BRAF assay and the CTA (i.e., bridging studies) to clinically validate the test as safe and effective for selecting patients who may benefit with dabrafenib and trametinib. GlaxoSmithKline had banked greater than 95% of the patient population from the respective trials. The specimen characteristics were summarized for tumor proportion, anatomical site, melanin content, necrotic tissue, fatty tissue, hemorrhagic tissue and whether macrodissection was performed, to aid in assessing any potential bias due to missing samples. In terms of analytical concordance, all available evaluable specimens (negative and positive) that were tested with the CTA informahealthcare.com

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were retested with the THxID BRAF test, and the comparison demonstrated greater than 90% agreement between the CTA and THxID BRAF test. Concordance on clinical outcome (investigator-assessed PFS) was assessed for patients enrolled in the trials whose tumors were V600E or V600K positive as detected by the THxID BRAF assay. The subset of total patients CTA-positive, both treatment arm and control arm) enrolled into the trial who tested positive by the THxID BRAF test was used to recalculate the hazard ratio (HR) based on the THxID test. The HRs for the subset of THxID BRAF tested subjects was similar to that from the randomized population for both dabrafenib and trametinib. The estimate for improved median PFS time was similar regardless of which test was used. Since the trial only enrolled marker positive patients, survival outcome data for the CTA-negative, THxID BRAF test-positive population was not known. Therefore, an array of possible HRs was considered for those patients who could be labeled mutation-positive by the THxID BRAF assay but wild type by the CTA (i.e., those excluded from the trial). Conditional probability was used to combine a postulated HR with the HR estimate in the trial for patients who were mutation-positive by both. The PFS HR for those patients positive by THxID BRAF assay but negative by CTA was allowed to range from the observed HR in marker positive patients to 1.0. Using these values, the estimate of the PFS HR including the THxID BRAF mutation-positive, CTA wild-type patients was calculated and was consistent with the PFS HR in the randomized population. Overall, the results from the bridging study provide a demonstration of the clinical validity of the THxID BRAF test to support the selection of patients whose melanoma tissue is BRAF V600 mutation positive for treatment with dabrafenib or trametinib [39]. Lesson learned: Successful bridging studies in marker-positive-only trials relies on availability of specimens from patients screened by the CTA(s), and excellent concordance to the CTA device prototype(s). Lessons learned about the importance of specimens

Central to any biomarker-based accrual of patients to a trial is the testing of the patient specimens. The FDA typically considers the specimen type to be a distinct part of the intended use of the device, and requires that a test is independently analytically validated for each specimen type within that intended use. Therefore, sponsors should specify the specimen type that will be acceptable. Specimen types are designated by their tissue origin (e.g., colon, lung, breast, blood), specimen preparation reagents (e.g., FFPE, freezing, anticoagulants), method of collection (e.g., surgical resection, fine-needle aspirate) and specialized collection devices, (e.g., PAXgene tubes, EDTA blood collection tubes). Currently, the FDA considers the need to validate primary versus metastatic tissue on a case-by-case basis, largely dependent on the trial design and test method, as well as published patient management guidelines. For example, differences in test performance in the detection of simple genetic mutations may not be a critical variable in primary versus 877

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metastatic (although the status marker itself may be stage dependent), but the performance of an IHC assay may be dependent on variables associated with the anatomic site, and gene expression signatures may significantly differ. Tumor characteristics are also considered for their potential impact on clinical decision points associated with the assay. Sponsors should assure that they have a specimen acquisition plan in place to acquire all necessary specimens, preferably from all patients screened for the trial. Notably in the 16 December 2008 ODAC meeting, expectations for having >95% of samples available for any retrospective analysis was considered a critical component of clinically validating biomarker claims [33,40]. Banking all intend to diagnose specimens is important in the event that the patient specimens need to be retested, for example, in a bridging study (discussed above). Sponsors should have a specimen banking plan that considers acquiring a satisfactory amount and number of specimens, should re-testing become necessary. It is also useful to collect specimens to support the specimens needed for additional analytical validation studies, although clinical specimens from the trial should not be used unnecessarily for certain analytical studies where procured specimens may suffice. When putting a specimen banking plan in place, appropriate informed consent and the conduct of trials in foreign countries that may not allow shipping of specimens outside the country should be planned for; otherwise, these issues may complicate any efforts to retrospectively use specimens should additional retesting be necessary. Pre-analytical steps and specimen protocols that involve macrodissection or additional purification steps (e.g., melanin extraction) should be outlined and be consistent across all testing sites. When banking the specimen, consideration should also be given to whether storage factors will impact any intention for future retesting. Sponsors should also attempt to capture all critical variables for each specimen that may be used to support test performance. These variables are used to demonstrate that there is no known imbalance between the specimens available for retesting and specimens that are missing, should retesting be necessary. Critical variables are those that can impact test results and are dependent on the technology, assay and analyte. For cancer IVDs, this includes sample characteristics such as primary or metastatic, stage and grade, tumor size, sampling method (biopsy or resection), percentage of tumor content in sample, including whether the sample was macrodissected, area of tumor tissue, amount of necrotic tissue, melanin content and age of specimen. Additionally, patient characteristics and stratification factors should be collected so as to minimize imbalance in co-variates that may impact efficacy should samples be missing in a bridging study. This may include, but is not limited to, the patient demographics such as age, gender, race; medical characteristics, months from first histological diagnosis to randomization and prior treatment regimens. Finally, sponsors should consider the types of analytical validation studies they may need to conduct and plan to collect the appropriate specimens. For example, for tests that are 878

intended to be conducted in either bone marrow or whole blood, it is useful to plan to collect paired specimens of each type from the same patient at the same time. Other examples include collection of blood in more than one type of anticoagulant tube, and collection for stability studies requiring more than one time point for blood collection. Expert commentary & five-year view

The FDA co-approval of therapeutic and companion diagnostics is an affirmation of the new era of personalized medicine; one that acknowledges that medicine is moving toward treatment of molecularly defined patient populations. As part of the approach toward therapeutic product success, pharmaceutical companies involved in therapeutic development for oncology therapy products, are quickly including companion diagnostics a part of their therapeutic development strategy with the hope of achieving a more efficient and successful study goal [41]. Simultaneously, however, this one-drug one-test model has also brought many scientific, economical and regulatory challenges that pharmaceutical companies, device manufacturers, clinical labs and regulatory agencies will have to work together to overcome. The growing trend in clinical trial design for cancer are ‘basket trials’, where specimens obtained from patients with a variety of cancers are tested to identify the presence of any mutation, and are then matched to investigational therapeutics which hold promise for that particular pathogenic pathway. With increasing information about the genetic basis for cancer and mechanisms of drug response, and the increase in the number of targeted therapeutic products, it is likely that tumor testing will grow to lead decisions about treatment regimens in the primary as well as metastatic setting. The rapid adoption of next-generation sequencing technology and expansion of available oncology sequencing panels in laboratories is evidence of these changes occurring now. The FDA held a workshop (can reference link to the workshop which will be posted after February 20) to discuss how to ensure the safety and quality of next-generation sequencing-related information without sacrificing scientific or clinical validation, in preparation for maintaining consistency with trends in patient management. Additional considerations to alternative less expensive testing that can be applied (e.g., ALK IHC vs ALK FISH) will also dominate therapeutic decision-making. It is in everyone’s best interest if multiple tests are available for the same therapeutic product as laboratories may not be able to purchase, install and validate multiple tests for the same analyte to cover several indications, or should the manufacturer of the original test cease production. To assist with this need, the FDA has been working on a path for marketing authorization of follow-on (or ‘me too’) companion diagnostics. The challenge with the follow-on tests is to ensure that the followon test identifies the same target population as the original approved companion diagnostic. For reasons outside the scope of this discussion, a method comparison study for concordance between the two methods may not be adequate as it fails to capture whether the discordance between the two methods Expert Rev. Mol. Diagn. 15(7), (2015)

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Lessons learned in companion diagnostics

would result in changes to conclusions about drug efficacy and safety in the follow-on test selected set of patients. In the case of genotyping assays, whether two tests would select the same patient population requires minimal consideration of key highlighted differences such as in specimen types that have been validated, analytical sensitivity and the alleles that are identified (e.g., the approved companion diagnostic tests to detect EGFR mutations in NSCLC patients differ for treatment with Tarceva (erlotinib), and Gilotrif (afatinib). The FDA continues to draft guidance documents, hold workshops and establish regulatory initiatives as part of the Agency mission to support faster therapeutic product approvals, and biomarker-tailored drugs. To date, the co-approval process has been a learning experience for both the Agency and Industry, and continues to evolve. Given the level of interaction

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needed for success, pharmaceutical manufacturers and their diagnostic partners are proactively recognizing that the diagnostic device and the therapeutic product are a development package, and that new approaches in development are critical. New trial designs and emerging diagnostic technologies will likely challenge the current regulatory paradigm, but they will bring the promise of greater benefit to cancer patients. Financial & competing interests disclosure

The authors are employees of the US FDA. The authors have no other 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 apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

Key issues .

A companion diagnostic development plan should be included as part of clinical development plan of the investigational therapeutic when biomarker-based conclusions about drug safety and efficacy are anticipated.

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It is optimal to use the final version of the test to screen patients for the trial.

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Drug and device claims rely on pre-specified device design, and analytical validation prior to initiation of a study is critical to planning patient enrollment.

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A plan for appropriately banking and annotating patient specimens (both test negative and test positive) and assuring storage does not impact test results is critical to future bridging studies.

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Regulatory paradigm is still evolving to address the challenges with new trial designs and emerging diagnostic technologies.

MedicalDevices/ ProductsandMedicalProcedures/ InVitroDiagnostics/ucm301431.htm?source %20=govdelivery

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