James Blakemore, Ph.D.
These emerging technologies offer huge potential to resolve issues.
The final cost of the Human Genome Project has been estimated at approximately $2.7 billion. At the time, researchers predicted costs would need to fall significantly to enable routine genome sequencing and usher in a new era of personalized and predictive medicine. In late 2001, at a scientific retreat convened by the National Human Genome Research Institute, the threshold cost of $1,000 per genome was conceived. Consequently, the “$1,000 genome” has been chased by DNA sequencing platform developers ever since.
With the recent launch of the HiSeq X Ten system, Illumina appears to have breached the $1,000 barrier to sequence a human genome in a single day. Illumina’s “$1,000 genome” claim is inclusive of instrument depreciation, consumables, DNA extraction, library preparation, and estimated labor. Although the exact cost is widely debated, this indicates a “real-world” figure rather than an abstraction of direct sequencing costs. In this context, it would appear that the personalized medicine era envisioned in 2001 has officially arrived.
In reality, the diagnostic requirements of personalized medicine—and the challenges of meeting these requirements—have become well understood by stakeholders during recent years. Increasingly, diagnostic tests are required to analyze multiple genomic or proteomic biomarkers of disease in a single test. An additional requirement is the need to apply these tests with increasing frequency to monitor disease progression and patient response to therapy.
One such example in the oncology field is the identification and ongoing characterization of new mutations along the epidermal growth factor receptor (EGFR) signaling pathway.
In addition, it is understood that patients will require a prospective genome analysis to narrow the choice of targeted drug therapy. One such application is epigenetic testing, to establish a patient’s predisposition to a particular disease, which often requires a genome-wide analysis. These emerging requirements have in common both an increase in the volume of patient testing required and the amount of actionable data each test provides.
The Current Scenario and Routine Testing
Molecular diagnostic systems are underpinned by a broad spectrum of technologies that have been the workhorse of personalized medicine for the last 15 years; arguably since the development of a companion diagnostic test to detect overexpression of HER-2 protein in breast cancer patients, and to direct use of trastuzumab (Herceptin; Roche). In certain therapeutic fields, notably oncology, significant limitations are emerging in the ability of conventional molecular diagnostic technologies to adequately serve the emerging clinical and commercial requirements of personalized medicine. In certain oncology applications, for example, the cost of a molecular diagnostic test kit plus the combined cost of associated pathology lab procedures is prohibitively expensive to some payers. When combined with extended turnaround time, this high testing cost further diminishes the value of the test. This scenario is occurring against the emerging requirements identified above for routine patient monitoring practices to establish patient response to therapy (or to identify drug resistance).
A central tenant of the $1,000 genome approach and the personalized medicine era is patient access to routine diagnostic testing. Routine diagnostic testing is vital to inform clinicians of patient disposition toward certain therapies, and to then monitor patient progress over a course of therapy. It thus follows that healthcare professionals will require routine access to affordable diagnostic systems providing actionable information derived from easy-to-use devices.
Given the limitations of existing diagnostic platforms outlined above, this proposed democratization of diagnostic technologies presents a significant challenge. The issue is multidimensional with technical, clinical, and commercial considerations. At Cambridge Consultants, we believe that wider access to diagnostic testing will be facilitated in part by the introduction of disruptive technologies. The value of introducing disruptive technologies in this area is exemplified by the plummeting cost of genome sequencing in recent years. These developments have set the course for the further introduction of novel technologies and platforms to resolve challenges raised by routine testing of patients.
Diagnostic companies will struggle to meet these new requirements with incumbent technology platforms. Multiplexed PCR systems are only able to assess a relatively small number of disease biomarkers; also, this approach fundamentally requires the analytical targets to be characterized prior to testing. This contrasts with the requirement for a broader analysis of the patient genome in order to identify gene mutations along key signaling pathways. Existing diagnostic systems may lack the sensitivity to provide this level of analysis, compared with more innovative approaches such as whole-genome or whole-exome sequencing.
In parallel with the maturing of the personalized medicine field, the last few years have seen the emergence of semiconductor-based technologies. Examples include Ion Torrent, DNA Electronics, and Oxford Nanopore. The semiconductor-based trend appears to continue with the interesting development of core diagnostic technologies by large semiconductor players traditionally on the periphery of life sciences instrumentation. Technologies developed by companies such as Panasonic, Hitachi, Samsung, Sony, and Intel demonstrate considerable potential to enable the democratization of diagnostic testing. Their proprietary technologies cover a wide area of the diagnostics space including DNA microarrays, single molecule DNA sequencing, PCR, and isothermal PCR. Each identified development represents a core detection technology around which a diagnostic platform could be created.
These resulting platforms would have the potential to enable fundamentally different diagnostic system architectures. This is exemplified in the Samsung PCR patent, which demonstrates a shift of functionality to the consumable, potentially resulting in an instrument of vastly reduced complexity. The elimination of a large instrument could shift the current value proposition in diagnostics (repeat consumables for an installed base of high-cost lab based instruments) and enable the technology democratization required for routine diagnostic testing in personal medicine.
These semiconductor-based platforms have the potential to address the technical, clinical, and commercial bottlenecks that need to be removed to facilitate the routine use of diagnostic technologies.
Resolution of Technical, Clinical, and Commercial Challenges
Technical considerations are addressed by the exploitation of “bottom-up” semiconductor fabrication methods enabling greater consumable functionality and leading to radically different diagnostic system architectures. Consumables with additional functionality fabricated within them enables smaller and less complex instruments. This leads to improved ease-of-use by nonskilled staff and thus greater availability of diagnostic testing for routine use. Clinical considerations are addressed by the use of existing life science techniques such as PCR, ensuring parity between tests used on existing diagnostic platforms and those tests carried out on new platforms.
Commercial considerations such as cost are readily addressed by semiconductor-based developments. By its nature, semiconductor manufacturing is organized around vast economies of scale. Manufacturers would be able to utilize significant existing semiconductor manufacturing facilities. The exploitation of Moore’s Law could also mean significant cost savings in the longer term as manufacturers utilize their experience of the consumer electronics industry with aggressive price pressures.
To expand market access to innovative diagnostic technologies will require collaboration between diagnostic companies and semiconductor organizations. Diagnostic companies have established routes to market and efficient distribution channels for their tests. The semiconductor companies bring disruptive technologies that facilitate improvements to clinical performance. This is apparent in recent diagnostic-semiconductor company collaborations.
A major focus of these semiconductor diagnostic technologies currently is analyte detection. This is not surprising as this aspect of the diagnostic workflow offers significant opportunities to enable disruptive technologies to make an impact. However, the entire workflow is ripe for innovation, notably the simplification and standardization of pre-analytical steps (e.g., sample collection and preparation) and more effective user interfaces for data capture and reporting of diagnostic information. These features, once consolidated into an integrated, semiconductor-based platform closer to those administering treatments, could form a powerful proposition in the era of personalized medicine.
Nick Rollings ([email protected]) is principal engineer, medical technology division, and James Blakemore, Ph.D. ([email protected]), is senior market strategy consultant, medtech consulting group at Cambridge Consultants.