In vitro molecular diagnostics have established themselves as effective tools for all aspects of disease management, especially in areas of unmet clinical need. Such tests have been developed for screening and prognosis as well as for applications, such as determination of genetic predisposition to disease, detection of presymptomatic disease, and prediction of individual drug response. Molecular diagnostics are the basis of pharmacogenomics, enabling the evolution of personalized medicine.
In Drug and Market Development’s (D&MD) recently published market assessment report entitled “Molecular Diagnostics: Effective Tools for Disease Management”, molecular diagnostics is taken to include tests for small-molecule, protein, or nucleic acid biomarkers and is mainly concerned with biomarkers that are measured using marketed clinical laboratory test kits or clinical analyzers. Biomarker assays are increasingly used throughout the process of disease management. A well-developed example is the use of HIV tests, including probe-based nucleic acid tests (NATs) for viral genotyping, in the management of AIDS patients.
Molecular diagnostic tests typically analyze key DNA, RNA, or protein biomarkers (analytes) to identify a disease, determine its course, evaluate response to therapy, or predict individual predisposition to a disease. The techniques applied involve analysis of DNA sequences, DNA methylation patterns, gene expression profiles, proteins, protein expression, or combinations of these biomarkers. Such biomarkers provide direct information about genotypic and/or phenotypic changes associated with specific diseases or responses to treatment. Biomarker analysis has also become an important tool in drug discovery, preclinical drug development, and patient monitoring during clinical trials.
Regulatory events of note during the last two years include FDA approval of the first DNA microarray instrumentation system for in vitro diagnostic use (Affymetrix’ GeneChip System 3000Dx) and the first highly multiplexed diagnostic microarrays: Roche’s AmpliChip CYP450 test and two cystic fibrosis tests—Tm Bioscience’s Tag-It and Osmetech’s eSensor. Although not yet approved by the FDA, tests based on transcriptomic profiling have also debuted successfully on the market.
The first generation of marketed molecular diagnostics have been based on established immunoassays and NAT technologies. Although the NAT market continues to be dominated by Roche, Abbott Laboratories and Bayer, many biotechnology companies have recently acquired significant IP property in this area.
The company leaders in immunoassay and NAT identified in the D&MD Report include Roche Diagnostics, Abbott Laboratories, the Ortho Clinical Diagnostics and Lifescan units of Johnson & Johnson, Beckman Coulter, Bayer Diagnostics, Becton Dickinson, Dade Behring, and bioMerieux. Important niche suppliers include Agendia, Bio-Rad, Biosite Diagnostics, Cepheid, Chembio Diagnostic Systems, Chiron (Novartis), Ciphergen Biosystems, Correlogic Systems, Cytyc, DiagnoSwiss, Diagnostic Products, Digene, DiaSorin, Epigenomics, EXACT Sciences, Gen-Probe, Genaissance Pharmaceuticals, HandyLab, Innogenetics, Interleukin Genetics, Matritech, Myriad Genetics, Nanogen, Nuvelo, Nymox Pharmaceutical, OXIS International, Proteome Sciences, Sequenom, SomaLogic, Sysmex, and Third Wave Technologies.
Current molecular diagnostics are primarily single-analyte tests involving the detection of a single gene or protein. However, many disease-related processes are multifactorial, involving the abnormal expression of multiple genes or proteins. Second-generation molecular diagnostics are anticipated to utilize novel detection technologies and multiplexing platforms to allow the measurement of a large number of analytes simultaneously. These innovations will increasingly utilize multiplexing platforms such as DNA microarrays that perform parallel biomarker analyses.
Market Considerations and Forecasts
The molecular diagnostic segments are projected to outperform the overall diagnostics market, growing from $13.8 billion in 2005 to $22.7 billion in 2010 (AGR of 10.4%), in contrast to the overall forecasted increase from $36.5 billion in 2005 to $53.6 billion in 2010 (AGR of 8.0%) for the entire IVD market.
Although the overall laboratory-based immunoassay segment is a mature market, the molecular diagnostics segment of the immunoassay market of $12.8 billion in 2005, is expected to increase at an AGR of 8.9% to $19.5 billion in 2010.
This immunoassay segment growth will result from tests based on recently validated biomarkers. One such growth opportunity example is in the cardiovascular disease drug therapy area where, currently, the relevant tests are only worth a few percent of the IVD market. Most tests relating to heart disease, e.g., cholesterol and triglycerides, are done on high-throughput clinical chemistry analyzers using small volumes of inexpensive reagents. Thus the large numbers of cardiovascular tests performed annually worldwide do not translate into large markets.
However, sales of the newer cardiac markers, which are immunoassays, are growing strongly. European growth rates in 2003 exceeded 35%. These molecular diagnostics, used in risk stratification and therapy monitoring, illustrate the increasing role of specific biomarkers in selecting and guiding drug therapy.
Sales for NAT’s are projected to grow more quickly than immunoassays. The NAT sector is currently very dynamic and is expected to grow from $1.1 billion in 2005 to $3.3 billion in 2010, an overall AGR of 24.2%. Notwithstanding their greater utility in many circumstances other than immunoassays, NATs are starting from a lower baseline (8% vs 92% of total molecular diagnostics sales in 2005, rising to 14% vs 86% in 2010) and will, to some extent, displace immunoassays in applications such as infectious disease testing.
Next-generation Molecular Diagnostics
The current molecular diagnostics products consist mainly of tests designed around a single biomarker associated with a disease state. Next-generation molecular diagnostics will employ multiplexing platforms, such as DNA or protein microarrays, to perform parallel biomarker analyses. Increasing automation and miniaturization, combined with new technologies that allow ultrasensitive quantitative multiplexed detection, is expected to increase sensitivity and reduce cost for many diagnostic applications. There are indications that the next advance will involve measuring several biomarker types simultaneously (for example DNA and protein).
Such innovations relate to constructs, such as DNA/antibody microarrays capable of assaying proteins and NATs simultaneously, or to immunoassays using nucleic acid labels, where the results are amplified and read via PCR. Such tests would allow immunoassays and nucleic acid tests to be performed on a single instrument. In principle, the user need not know what type of test was being utilized for any given assay.
Also observed is a growing trend from low- to high-margin molecular diagnostics as developers have become more concentrated and have capitalized on patent-protected protein and gene-based biomarkers. This should make investment in molecular diagnostics more attractive to investors.
Innovation in the molecular diagnostics area appears to be robust as demonstrated by an analysis of issued patents and published patent applications from January 2000 to September 2006.
The Rise of Companion Diagnostics
Biomarkers used in the drug development process can be developed into diagnostic tools to identify a patient population for a particular drug and potentially provide information that is more dynamic, sensitive, and specific for disease progression and second-generation modifications to the drug of interest. Many drug companies are evaluating business models based on molecular diagnostics for pharmacogenomic testing as the driving force behind the shift toward personalized medicine. A number of hurdles confront the personalized medicine model, including regulatory policy, patient-provider cost coverage, and patient record privacy.