Feature Article

Developing and Commercialising Companion Diagnostics

Posted in IVD by Camilla Andersson on September 27, 2011

An overview of the technology and key success factors of companion diagnostics, including case studies highlighting
the challenges of developing viable products.

Companion diagnostics (CDx)—tests used to ensure that prescribed drugs will be safe and effective for particular patients—have been hailed as driving an impending revolution in medicine. However, most CDx developers must overcome a variety of hurdles if they are to achieve developmental and commercial success in a complex and rapidly changing medical landscape.

In this article, we provide an overview of major current and next-generation CDx and consider the technological requirements for their successful development and commercialisation. Case studies of the well-known CDx products Her2/Neu and Trofile are presented to illustrate the challenges faced by CDx developers. Our focus is on in vitro diagnostic tests and technologies/methodologies for companion diagnostics employed in clinical settings to enhance safety, efficacy and responses to therapeutic treatment. We do not address technologies used in discovering or identifying companion diagnostic biomarkers or CDx technologies employed for drug discovery.

Current and emerging technologies in companion diagnostics (CDx)
Diagnostics developers often must choose among many methods for detecting biomarkers. Deciding which technology to use depends on the biomarker’s characteristics, the measurements required and how the diagnostic will be used. For example, in oncology, when the target gene can be mutated in many different ways and if clinical samples contain a high fraction of neoplastic cells, direct or indirect sequencing methods might be most appropriate in order to detect all possible mutations. By contrast, if there are only one or a few known mutations, polymerase chain reaction (PCR) is generally easier and cheaper.

The pros and cons of each technology must be carefully evaluated in order to determine which will best show whether a specific prescription drug will be safe and effective for a specific patient.

Emerging technologies
Next-generation technologies are expanding the applicability of sequencing. Methods now in the pipeline will offer higher throughput and lower price per base compared with traditional sequencing and can perform millions of reactions concurrently. Advances in data processing and storage are making these technologies more amenable for use in clinical diagnostics.

For example, single molecule sequencing enables analysis of genomic information from small amounts of DNA without the need for amplification, thus enabling data generation in a few hours instead of the days or weeks required for traditional sequencing. Greater efficiency is likely to be a key driver in the adoption of next-generation sequencing technologies for companion diagnostics.

Other technology advances, such as quantitative histopathology, quantum dots (QDots) and digital pathology will propel older protein detection technologies such as IHC to the forefront of CDx. 

  • Quantitative histopathology technology provides for the measurement and localisation of protein biomarkers in tissue. An automated fluorescence-based imaging platform is used to identify and quantify tissue biomarkers in either a high-throughput tissue microarray format or in tissue slices. 
  • QDots linked to antibodies and applied to tissue sections can be designed to produce many discrete wavelengths of fluorescent light with minimal spectral overlap, thus achieving a high order of multiplexing while preserving an ability to visualise cell structure and tumour architecture. 
  • Digital pathology will enable better standardisation and quality control in the interpretation of immunohistochemistry (IHC), thus minimising pathologists’ tendency to falsely overcall samples and alleviating the need for additional tests or methods to ensure quality.

Key success factors for a companion diagnostic test
In order to successfully develop and market CDx, companies must address a variety of key factors that will encourage routine, widespread use of their products.

Successful development requires availability of material suitable for testing; biomarkers predictive of a therapeutic response; and accurate, cost-effective techniques for detecting the biomarkers. As mentioned above, selection of the appropriate technology depends on the type of biomarker to be detected.

Adoption and commercial success of a CDx technology require, among other attributes: flexibility in handling clinically relevant body fluids and tissue biopsy samples; cost-effectiveness and scalability in relation to clinical demand; accuracy, reliability and efficient turnaround time; and, the ability to multiplex efficiently in light of patient-to-patient heterogeneity and the limited utility of single biomarkers.

The business ramifications of hitting key success factors
For even the most successful CDx companies, providing tools to enhance the use of therapeutics is no simple matter; many companies struggle to meet key developmental and commercial success factors. Case studies of two well-known CDx, HER2/Neu (developed by a variety of suppliers including Dako and Abbott and sold along with Genentech’s Herceptin) and Trofile, developed by Monogram Bioscience (sold along with Pfizer’s Selzentry), illustrate how new knowledge, changing technologies and the need for scalability of technology influence effectiveness, widespread CDx use and diagnostic and therapeutic sales.

Case study: HER2/Neu-Herceptin1, 2, 3, 4
Herceptin treats HER2-overexpressing metastatic breast cancer. When the drug was still in clinical trials, an IHC test, HercepTest, was developed and approved essentially simultaneously with Herceptin in order to identify populations that would best respond to the drug. Once Herceptin was approved, studies showed that, because IHC is not quantitative and there was high variability in reagents, test results were often inaccurate and that different labs had different rules for classifying positive and negative HER2 status. Moreover, there was heavy discordance when the results were borderline (that is, not strongly HER2-positive or HER2-negative). In some cases, tissue from one area of a breast cancer tested HER2-positive and tissue from a different area of the cancer tested HER2-negative. This was largely caused by high variability in IHC reagents, protocols and laboratory interpretations. As a result, Genentech and clinical laboratories had to rely on the evolution of more reliable but indirect measurements such as fluorescence in situ hybridisation (FISH). But FISH, which quantitatively measures gene copy number, is expensive and requires additional equipment and training that most laboratories lack. As a result most laboratories still use only IHC.

Because inaccurate HER2 test results may lead to inadequate care, in order to prevent false negatives, some laboratories that primarily use IHC retest with FISH when IHC results are unclear or borderline. However, this dual strategy fails to measure the activity of HER2 pathway directly and provides inaccurate results in 20% of cases.4 The optimum CDx for HER2 would directly measure the activity state of the HER2 protein. Furthermore, it should require minimal expertise to interpret the results. None of the current tests fulfill these criteria.

New technologies such as Monogram’s (now Labcorp) proximity assay, and Ventana’s (now Roche) recently approved dual in situ hybridisation (ISH) assay, may be important in making HER2 testing more reliable. Standardised digital IHC also may help reduce variability among laboratories. The Ventana assay allows visual counting of the number of HER2 gene copies on chromosome 17 under a microscope. Based on a staining system that colours chromosome 17 red and the HER2 gene black, it is easier to use than a FISH test. Additionally, the assay makes the HER2 and chromosome 17 copies visible for longer periods. However, further investigation and validation will be required to determine whether such technologies accurately measure HER2 amplification. Given the high cost of Herceptin, its side effects, and the life-threatening nature of the disease, developing more accurate CDx and evaluating them in well-designed clinical trials will be critical. Until this happens, erroneous treatment of breast cancer patients will continue and result in increased healthcare costs.

Case study: Trofile-Selzentry
Selzentry is an antiviral medication used with other medications to treat HIV patients. Classified as a CCR5 co-receptor antagonist, it works by slowing the spread of HIV in the body. A tropism test is a blood test that reveals how HIV enters T-cells and which receptors the virus uses. Tropism testing is necessary if Selzentry is to be included in an antiviral regimen. Selzentry is effective against CCR5-using HIV only. Tropism testing should be done to help determine if Selzentry is going to work.

Monogram Biosciences’ Trofile assay is a complex co-receptor tropism test that predicts response to Selzentry. Trofile is an unusual case because the pharmaceutical company Pfizer codeveloped the assay with the developer, Monogram Biosciences (now Labcorp). Pfizer invested US$25 million in Monogram Biosciences to develop the Trofile test, and currently markets the test with Selzentry. Monogram was the sole provider of the test, partly because the test required specialised expertise not available in routine clinical laboratories.

However, the test’s lengthy 18-day turnaround time inhibited widespread adoption. As test volumes increased and worldwide roll out of Selzentry began, Pfizer and Monogram faced both scale-up and adoption problems and third-party payers were slow in agreeing to reimburse for the test, further slowing adoption. As a result, despite co-development and a strong Rx-Dx partnership, Selzentry sales fell short of expectations.

In conclusion, many CDx technologies are available today and exciting new technologies such as next-generation sequencing are on the horizon. To create effective tests, companion diagnostics developers must carefully select technologies based on the characteristics of the particular biomarker and on how the diagnostic will be used. To ensure routine, widespread adoption, they must thoroughly evaluate the pros and cons of the technology and make sure that the key factors of accuracy, reliability, cost effectiveness, turnaround time and scala-bility are consistent with clinical demand.

1. N. Papadopoulos, K.W. Kinzler, B. Vogelstein, “The role of companion diagnostics in the development and use of mutation-targeted cancer therapies,” Nat Biotechnol., 24, 8, 985-995 (2006).
2. W.H. Koch, “Technology platforms for pharmacogenomic diagnostic assays,” Nat Rev Drug Discov., 3, 9, 749-761 (2004).
3. A.C. Wolff et al., “American Society of
Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer,” J Clin Oncol, 25, 1, 118–145 (2007).
4. College of American Pathologists, HER2 Testing Guidelines, Accessed 23 February 2009.


Aruna Rajan
is Senior Associate,
Michael Jacobson
is Manager,
Kerry Xie
is Senior Analyst and
Harry Glorikian*
is Managing Partner at Scientia Advisors
55 Cambridge Parkway, Suite 300E,
Cambridge, MA 02142, USA
tel. +1 617 407 5093

* to whom all correspondence should be sent

A recent post on the EMDT blog medtechinsider.com recently discussed companion diagonostics and an upcoming UBM Canon tradeshow on clinical diagnostics. Read more in the medtechinsider post Diagnostica Europe 2012.

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