Companion diagnostics blaze a path for personalized medicine

By Craig C. Foreback, PhD

FDA defines a “companion diagnostic” as a medical device—often an in vitro diagnostic device—that provides information essential for the safe and effective use of a corresponding drug or biological product. Such tests help determine whether the patient benefits of a particular therapeutic product will outweigh any potential risks or serious side effects.

Companion diagnostics can identify patients who are most likely to benefit from a particular therapeutic product (theranostics), identify patients likely to be at increased risk for serious side effects as a result of treatment with a particular therapeutic product, or monitor response to treatment with a particular therapeutic product for the purpose of adjusting treatment to achieve improved safety or effectiveness.1

Tom Hayhurst, BioNano Genomics.

Tom Hayhurst, BioNano Genomics.

Companion diagnostics are an indispensable component of personalized medicine, and they are certain to increase rapidly in number and in the breadth of their application to disease areas.2 “As we profile an individual’s genome, we better understand what each individual inherits pertaining to their health,” says Tom Hayhurst, process leader for commercial operations at BioNano Genomics, San Diego. “This genetic profile has the potential to direct all medical decisions.”

The FDA definition does not state the type of diagnostic tests that are considered to be part of a companion diagnostic. Any in vitro diagnostic (IVD) test is eligible to be part of a companion diagnostic, although molecular diagnostics has generated the most excitement. Companion diagnostics have been shown to increase the safety and effectiveness of targeted cancer therapies in a number of neoplasms including B-cell non-Hodgkin’s lymphoma, breast cancer, chronic myelogenous leukemia, colorectal cancer, and lung cancer.3–7


Although most companion diagnostics research has so far been focused on oncology, biomarker exploration and research is now expanding to include Alzheimer’s disease, aortic valve disease, asthma, cystic fibrosis, hepatitis B, and rheumatoid arthritis.6,8

In most instances, observes Hayhurst, “the development of a companion diagnostic is the result of a collaboration between the developer of an IVD test and a pharmaceutical company that is developing a drug that targets a specific disease.”

Advanced technologies such as the MALDI Biotyper CA by Bruker are ushering in a new paradigm for companion diagnostics.

Advanced technologies such as the MALDI Biotyper CA by Bruker are ushering in a new paradigm for companion diagnostics.

Companion diagnostics can be developed after a drug has been marketed. But the more favored route is to codevelop the diagnostic alongside the targeted drug. High-throughput testing platforms are gradually replacing traditional instrumentation. Next-generation sequencing at the molecular level and matrix-assisted laser desorption/ionization–time-of-flight mass spectrometry (MALDI-TOF MS) at the proteomics level offer novel approaches to companion diagnostics.9 The use of such advanced technologies is ushering in a new paradigm for companion diagnostics termed “next-generation companion diagnostics.”3

Traditional diagnostics that rely upon tissue biopsies represent a significant obstacle to the concept of a companion diagnostic. To obtain enough information for reliable assessment of a suspicious mass, the pathologist may require a significant amount of tissue from the site. Moreover, since single biomarker examinations often review only a narrow section of tissue, multiple examinations using tissues from different portions of the site may be needed.

Such a heavy demand for more tissue specimens is problematic almost from the very start. Regardless of how they are obtained, tissue biopsies are inherently invasive, and they carry a risk of infection or other complications for the patient. In many cases, the patient’s poor condition makes the procedure too risky. And if the less-invasive approaches of core needle biopsy or fine-needle aspiration are used, there may not be enough tissue to perform pathology and histology examinations as well as molecular companion diagnostic testing.9 Testing for advanced lung cancer often suffers from inadequate samples, because the tumor or metastasis is in a part of the lung that cannot be accessed.

Other factors that challenge the effectiveness of companion diagnostics include preanalytical and analytical variables that are likely to alter biomarker results; inadequate assay validation or in-production quality control tools; inadequate or immature understanding of the biology or pathophysiology of a therapeutic target; misinterpretation of biomarker data owing to unfamiliarity with the technology; and an inadequate number of observations.10 To ensure that test results can support efforts to make use of companion diagnostics, clinicians, pharmaceutical companies, and in vitro diagnostics manufacturers each need to have a better understanding of the biology and limitations of the preclinical models, preanalytical variables, and analytical discrepancies.11

If a diagnostic test is inaccurate, the treatment decision based on that test may not be optimal. To ensure analytical accuracy, it has been proposed that FDA commission the College of American Pathologists to instate a certification process for clinical laboratories desiring to provide next-generation companion diagnostic assays.3 A laboratory receiving accreditation would be designated as a certified advanced companion diagnostic facility (CACDF).

The perceived advantages of CACDF status would be a lab’s involvement in enhancing patient safety in clinical trials to select biomarkers; reducing the variability of testing to an FDA-approved limit for a targeted therapy; and a shorter path to FDA approval of a targeted therapeutic agent evaluated in a CACDF laboratory.

As an alternative to dependence on tissue biopsies, researchers have recently determined that it is possible to detect indicative cancer-related mutations by analyzing intact cells and cell-free nucleic acids that circulate in the bloodstream and elsewhere. Solid tumors can shed intact cells, or microvesicles, as well as cellular components, such as nucleic acids (resulting in cell-free DNA or RNA) in the bloodstream. Circulating cell-free tumor DNA is suspected to come mainly from dead tumor cells.

Such “liquid biopsies” can provide earlier diagnostic data, avoid large tissue sample requirements, minimize repeat biopsies, and improve outcomes through the use of companion diagnostics.


The scope and applications of precision medicine are just beginning to evolve, building in part on the continuing growth and elaboration of complex new clinical and molecular diagnostic tests. Genetically guided therapy management is a rapidly emerging precision medicine application that uses an individual’s unique genetic makeup to help determine their most effective drug therapy.

For clinicians, a major stumbling block to the implementation of such precision medicine strategies is the sheer magnitude of the information to be mastered. The National Library of Medicine’s Genetic Testing Repository currently includes records for more than 31,000 discrete tests, involving some 5,800 conditions and 3,900 genes, which are now available to aid in diagnosis and selection of therapies.12 But managing and interpreting such a large volume of testing options and outcomes can easily be overwhelming.

The unfortunate result is that diagnostic tests are often improperly utilized, and therapeutics are improperly ordered. Studies have shown that physicians order the wrong test in up to 30% of cases, potentially leading them to order inappropriate therapies based on the test results.13

To help overcome these barriers to the use of precision diagnostics, two leading companies serving the molecular diagnostics market are combining their capabilities to create new tools designed especially for use by clinicians. The new effort brings together the clinical laboratory workflow and information systems expertise of Xifin Inc, San Diego, with the pharmacogenetic decision support tools of Translational Software, Bellevue, Wash. The partners’ integrated solution transforms raw genetic test results into actionable reports that clinicians can use immediately to determine the safest and most effective patient treatments.

Xifin, which launched more than a decade ago as a cloud-based financial system for large diagnostic labs, provides health economic optimization solutions for a diverse set of diagnostic service providers, including 7 of the 10 largest clinical laboratories in the United States. The company has a strong position in the molecular diagnostics testing market, processing more than 60% of all molecular testing claims nationwide and providing technology solutions, consulting and commercialization services, and industry advocacy to support the complex molecular diagnostics laboratory business environment.

Photo WhiteLale_2011

Lale White, Xifin.

“Genetic testing is one of the most rapidly growing segments of the molecular diagnostics market, and with it comes the growing need to manage vast quantities of genetic information and develop the systems infrastructure needed to support personalized medicine initiatives,” says Lâle White, CEO of Xifin. “Our collaboration with Translational Software is a big step in our strategy to help molecular diagnostics companies and laboratories increase the efficacy of treatment decisions and drive value-based decisions that truly improve health outcomes. This partnership will also be instrumental in helping our customers bring new genetic tests to market quickly, dramatically reducing time-to-market for new testing services.”

Translational Software’s cloud-based service for molecular diagnostic laboratories incorporates guidelines from pioneering efforts in pharmacogenetics and integrates those decision support capabilities into laboratory and clinical information systems. In 2013, the company launched services that enable laboratories to enter the rapidly growing field of pharmacogenomics, and it now serves more than 60 active laboratories.

The company’s software platform automates the reporting process for genetic testing by matching test results to a knowledgebase of evidence for clinical genetics. The knowledge base includes treatment guidelines based on curated data gathered from consortia and professional society recommendations, regulatory filings, literature reviews, and other sources. The company’s completed reports focus on genetic factors that affect the efficacy and toxicity of many drugs, as well as risk factors relevant to the patient’s health, in order to guide clinical decisionmaking.

Don Rule, Translational Software.

Don Rule, Translational Software.

“We know how challenging it is for clinicians to analyze and interpret the raw data that pharmacogenetic testing generates, and to turn that information into meaningful intelligence to help guide effective patient treatment decisions,” says Don Rule, CEO of Translational Software. “One of our objectives in working with Xifin is to help make genetic testing a cost-effective tool for clinicians by automatically linking a patient’s genetic make-up to specific clinical guidance, and making this a routine part of the clinical care process. Using a genetic-based clinical decision support capability as part of the lab’s routine workflow will accurately predict how a given patient will respond to a particular drug, which will in turn improve treatment, reduce costs, and save lives—the real promise of personalized medicine.”


Contributing to the development of personalized diagnostics, the MiSeqDx next-generation sequencer by Illumina.

Contributing to the development of personalized diagnostics, the MiSeqDx next-generation sequencer by Illumina.

Illumina Inc, San Diego, is a leading company in the development of next-generation sequencing (NGS) technology. As an underpinning for the creation of targeted cancer therapies, Illumina is partnering with a number of major pharmaceutical companies to develop a universal NGS-based oncology test system for use during clinical trials. Illumina’s collaborators in the effort include AstraZeneca, Janssen Biotech, Merck Serono, and Sanofi.14

Rick Klausner, MD, Illumina.

Rick Klausner, MD, Illumina.

In parallel, Ilumina continues to collaborate with the key thought leaders of the Actionable Genome Consortium (AGC) to set standards for NGS-based assays in routine clinical oncology practice. “The AGC represents an extraordinary gathering of experts and decision-makers in clinical and molecular oncology, pathology, and technology who, by proposing the standards by which every tumor will be sequenced, will move the field of clinical oncology into the era of precision,” says Rick Klausner, MD, former director of the National Cancer Institute and current senior vice president and chief medical officer at Illumina. “Widely available, standardized genomic testing of tumors can be the means by which precision oncology, and therefore precision medicine, begins to live up to its promise.”15

In July, Roche Molecular Systems, Pleasanton, Calif, announced that it was filing a premarket approval submission with FDA for a companion diagnostic developed in collaboration with AstraZeneca.16 The partnership was launched in 2014 with the goal of developing a companion diagnostic for use with tissue and plasma specimens to identify non-small cell lung cancer (NSCLC) patients eligible to receive AZD9291, AstraZeneca’s third-generation epidermal growth factor tyrosine kinase inhibitor, which is currently under development. The collaboration also enabled Roche to investigate molecular analysis of less-invasive samples—including circulating tumor cells—as a means of guiding targeted cancer therapy. Roche Molecular Systems is continuing to collaborate with Roche Pharmaceuticals to develop companion diagnostics using plasma-based markers, and corresponding targeted therapies.

Leading the way in the development of clinical proteomics, Biodesix, Boulder, Colo, offers a protein-based diagnostic test called Veristrat, which is performed using MALDI-TOF MS. It is among the first tests to analyze a patient’s phenotype instead of their genotype. First developed for patients with advanced NSCLC, Veristrat provides a quick diagnostic test that can help oncologists prescribe second-line therapy choices. In a recent study, test-guided selection of Tarceva (erlotinib), developed by Genentech, was studied versus single-agent chemotherapy.17

Siemens Healthcare Diagnostics, Tarrytown, NY, has entered into a collaboration with Janssen Pharmaceutica NV, Beerse, Belgium, to design, develop, and commercialize a companion diagnostic test associated with an early-stage compound being developed by Janssen. The compound targets autoantibodies directed against the human ?1-adrenergic receptor (?1-AR) that could contribute to the development of heart failure. Under the agreement, Siemens Clinical Laboratory will work with Janssen to design immunoassay-based companion diagnostic tests for use in Janssen’s clinical studies. Siemens will develop and validate a companion in vitro diagnostic for the Janssen therapeutic product.

Trevor L. Hawkins, PhD, Siemens Healthcare Diagnostics.

Trevor L. Hawkins, PhD, Siemens Healthcare Diagnostics.

Siemens has also entered into a master collaboration agreement with Pfizer to design, develop, and commercialize diagnostic tests for therapeutic products across Pfizer’s pipeline. Under the agreement, Siemens will be one of Pfizer’s collaboration partners to develop and provide in vitro diagnostic tests for use in clinical studies and, potentially, global commercialization with Pfizer products.

“Our relationship with Pfizer marks a major milestone in Siemens’ personalized medicine strategy,” says Trevor L. Hawkins, PhD, senior vice president for strategy and innovations at Siemens Healthcare Diagnostics. “We look forward to collaborating with Pfizer to realize the goal of advancing innovative solutions that change the way patient care is delivered and, together, shape the future of diagnostic medicine.”


Experts within and beyond the clinical laboratory community believe that next-generation companion diagnostics have the potential to bring to reality the revolutionary promises of personalized medicine. Already, in vitro diagnostics manufacturers and pharmaceutical firms are becoming active partners in the codevelopment of companion diagnostics, which will be essential for guiding the targeted therapies of the future.

Clinical laboratorians will also have important roles to play in achieving the promise of companion diagnostics and personalized medicine. With more and more tests making use of advanced technologies such as NGS and mass spectrometry, lab professionals will need to be prepared for significant changes in the not-too-distant future. Staying on top of technology advances now will help laboratorians to be better advisors to physicians and their patients when there is a need to understand the nuances of tests being used to guide patient therapies.

Craig C. Foreback, PhD, is a contributing writer and member of the CLP editorial advisory board. For further information, contact chief editor Steve Halasey via [email protected]. 


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