Can Rapid Mobile Diagnostics Speed Up Clinical Trials And Regulatory Reviews?
By Wayne Koberstein, contributing editor, Life Science Leader
No industry trend is more promising, and yet more conflicted, than personalized medicine (PM). In its rationale, PM is almost logically invincible; who can argue with matching individual patients with medicines to which they are most likely to respond? But in practice, despite citable though qualified successes, the rationale often breaks down. Expensive and complicated tests, gaps in companion-diagnostics regulation, meandering business models, tiny patient segments, and record-high prices as the apparent trade-off for volume sales all tarnish the beauty of PM logic.
So, it is natural to be a bit skeptical when a new voice comes on the scene to proclaim another technological revolution in the PM sphere. That voice belongs to Dr. Anita Goel, CEO of Nanobiosym, who combines her business message with a grand vision of global medicine transformed by what she calls “nanodiagnostics.”
Nanodiagnostics is an accurate term in Goel’s case, because her company’s Gene-RADAR chip, developed so far primarily through U.S. defense and other federalgrants, probes DNA molecules at the nanometer scale. “What we are doing in our Gene-RADAR is using a very high degree of precision control with nano-scaled schemes to control DNA molecules, and the nano motors that read and write information into the molecules enable controlling them on very precise scales to achieve faster, better, cheaper readouts of the DNA.”
But the “nano” label does not apply to all single-unit, nonlaboratory diagnostic tools now in development. Thus, here we use the more widely applicable term “rapid mobile diagnostics” (RMDx) to encompass all the micro, milli, and other portable-scale Dx technologies. (Another, less-specific term in general use is “point-of-care” diagnostics.) And, as a new technological space containing all the alternatives, the most practical and immediate application for RMDx may be in clinical trials.
Beyond portability and speed, many RMDx technologies also claim higher accuracy than current lab-based, ELISA (enzyme-linked immunosorbent assay) tests. Some of the new technologies, like Gene-RADAR, vie to replace the old light-sensing, antibody-targeted assays with much more accurate but ephemeral DNA detection, thereby also dethroning PCR (polymerase chain reaction). Other RMDx devices measure non-DNA indicators of drug response and disease status, such as oxygen molecules. Microfluidics is a popular platform, but new modes, such as MRI or LCD technology, are always popping up. In an ideal world for all RMDx developers, their technologies would spread across the entire clinical spectrum, from research to mainstream treatment.
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“There are two big trends in medicine. One is the personalization of medicine, and the second is the mobilization of medicine.”Dr. Anita Goel, CEO, Nanobiosym |
Goel and others in the RMDx space maintain the technology could speed up trials and regulatory reviews by quickly selecting ideal patients and expediting the collection and analysis of patient response data. For regulators, the review process would operate in a higher gear thanks to the higher-quality data and higher benefit-risk ratios as predicted by the patient selection. “You find patients in a target population before you enroll them in a clinical trial, and you accelerate the drug development process, decreasing the cost and time in getting FDA approval, because you’ve focused your patient population in such a way, based on their biomarkers, that they will be more likely to show increased efficacy and decreased toxicity,” says Goel.
A WORLD OF PLAYERS
In a nutshell, Nanobiosym’s initiative spans all the possible fields of play in the RMDx game, from research to fighting the world’s worst epidemics. But its Gene-RADAR technology has plenty of competition from other companies, platforms, products, and applications. In addition to an untold number of small, entrepreneurial companies, large medical-device makers like Roche, Abbott, and Siemens are developing RMDx. To gather a core sample of the lesser-known startups, we spoke with several other companies for this report — Rheonix, T2 Biosystems, and SuperNova Diagnostics — each with its own unique platform.
Although every new technology may have its own list of initial disease targets, most aim for maximum flexibility in customization, so it is likely many of them will overlap in promise and in practice. Some developers share Goel’s vision that RMDx use in the developing world will lead to its adoption in the developed world; others do not. But essentially all players agree that commercial competition in the major markets will ultimately shrink the field.
Clinical trials logically present the first large competitive space for RMDx technologies. Diagnostics in general already have wide use in clinical development; a simple search for “diagnostic test AND drug” on ClinicalTrials.gov yields 2,979 trials, with the top areas being Infection (e.g. HIV, malaria, tuberculosis), Cardiovascular (CHD, COPD), Gastrointestinal (IBS), Renal (transplant rejection), and Cancer. One RMDx-specific study, “Introducing Rapid Diagnostic Tests Into the Private Health Sector,” aims to show how the technology can reduce overuse of anti-malarial drugs in Uganda.
Because most of the trials involving diagnostics are early to mid-stage, it is impossible to know how many of them will eventually lead to commercial drug/diagnostic combinations. But the gap between the number mentioned above and the mere 44 studies listed when “companion” is added to the search term — even allowing for the vagaries of text-string searches — suggests many more Dx tests are in use as adjuncts to trials than as part of a commercial combination in development.
Adopting RMDx to replace lab tests in clinical studies is arguably the next logical step. It is easy to see how handheld Dx devices, perhaps entrusted to the patients during a study’s active phase, could bring vast improvements over current tests in patient selection and monitoring alone — thus a huge potential exists for their use in trials. Similarly, RMDx could help investigators screen patient candidates more quickly and, maybe, less expensively. So the case for its superior efficiency, speed, and cost savings seems to rest on solid reasoning, if only in potential.
Yet, here as in proverb, the devil may reside in the details. Given the great range of testing targets, methodologies, and data types among all the competing platforms, the future for RMDx companies, users, regulators, insurers, and targeted patients remains unclear. Meanwhile, somewhat ironically, the most impeding factor in RMDx progress may be the imposing variety of alternative technologies it presents.
Certainly, faster, cheaper, more accurate diagnostics could be a key component of personalized medicine, starting in clinical trials. But according to Dr. Vicki Seyfert-Margolis, the FDA Commissioner’s senior advisor for regulatory science and innovation, the greatest challenge in PM is understanding disease causality — matching therapeutic mechanism-of-action with patient-specific mechanism-of-disease through accurate interpretation of the related biomarkers.
Where those relationships are well understood, some advanced diagnostics are already in use; however, a vast area remains where diseases continue to confound us and thus RMDx may find use mainly as a research tool. Many conditions may never yield to personalized targeting. Still, much the same could be said for many supportive technologies meant to speed drug development; applying them more widely and effectively will require greater understanding of disease mechanisms.
Promisingly, many of the RMDx platforms in development offer advanced immunoassays — one possible key into the great unexplored territory of immune/inflammatory response to disease. Signaling a shift in the PM model, Seyfert-Margolis stresses the need to “go well beyond genes and gene variance” to understand the immune system’s role “not only in the initiation, but in the maintenance” of diseases.
SPICE OF VARIETY
Rheonix represents the comprehensive, one-stop-shopping model of RMDx. The company is developing “a highly customizable diagnostic platform that can run both user-designed and FDA-cleared assays” for infectious diseases, cancer, pharmacogenomics, and water testing. Rheonix claims its “milli-fluidics” Encompass platform, a portable work station, and its CARD system, a disposable multi-sample cartridge, “provide significant cost-savings, allowing for universal adoption of mobile diagnostics.”
In configuration, the Rheonix system typifies most of the RMDx systems at this point. Rather than the single “Star Trek” tricorder-like unit envisioned for the future, it consists of several separate units, including a briefcase-sized base station. But, like most other RMDx developers, Rheonix has a self-contained desktop device in prototype to replace its larger but still portable system. Again, it is in prototype — the word indicates the real state of the technology at this point. Further miniaturization to handheld scale, albeit along an uncertain timeline, could expand use beyond doctors and nurses to patients or others with little or no medical training.
The question is, which RMDx platform is best suited to leading the charge? Opinions depend, of course, on each developer’s interest and viewpoint. Yet a comparison of developers’ competing positions can be informative.
One critical issue in the race, maintains Rheonix President Tony Eisenhut, is sample size. Not all conditions are amenable to nanoscale measurement, he says. “To catch or identify an infectious agent or cancer biomarker early, you’re looking for the needle in a haystack, and the likelihood of finding the target in a nano-size sample is highly unlikely. So from a clinical standpoint, there are often times where you want a large sample in hopes of capturing the actual agent or marker you’re looking for.”
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“What we’re finding is that the majority of the tests that physicians, nurses, and patients really want in a PoC format can’t be miniaturized or made into a clinical-care format because of limitations with current PoC technologies.”Neil Campbell, president and CEO of SuperNova Diagnostics |
Eisenhut also emphasizes the need for RMDx systems to be easily customized for various biomarkers and disease indications, to deliver significant cost savings over current systems, and to take advantage of electronics-industry style production of expendable components. Given those constraints, he sees room for more than one platform in the field.
“My personal belief is that there’ll be multiple players, perhaps up to six players, in the marketplace,” he says. “A couple will be very specialized, maybe oncology-focused, a couple infectious disease-focused, and a couple will bridge infectious disease and oncology, pulmonary, cardiac, or anything that involves moleculargenotyping assays.”
T2 Biosystems addresses another potential differentiating factor in the RMDx field: sample preparation for maximum efficiency and speed. To challenge the mainly optical-based tests currently in use, the diagnostic tool in development by T2 Biosystems uses tiny magnets in a miniature MRI device to measure how oxygen molecules react in the presence of magnetic fields. Detecting unique signatures within complex bioreactions, the T2 system delineates pathogens, genomics, and protein and small-molecule immunochemistry. It may be unique or at least among the few systems that handle raw samples, eliminating expensive purification.
Such refinements, which primarily serve to speed up the process, will be most useful in the PoC environment, where the technology must be conducive to physician or patient use, as in clinical trials. Yet some in the business question the handheld concept, at least to a degree.
“Although we have a preproduction prototype to address the shortcomings of PoC, the current problem is if you want to do PSA for prostate cancer or biomarker tests for other cancers and infectious disease, you can’t do those types of tests in a handheld format to the standard of the central lab,” says Neil Campbell, president and CEO of SuperNova Diagnostics. “What we’re finding is that the majority of the tests that physicians, nurses, and patients really want in a PoC format can’t be miniaturized or made into a clinical-care format because of limitations with current PoC technologies.”
Still, with its portable set of sample collector/processor, analytical disposable, and the readout device, the company still aims to “move the laboratory into the palm of your hand.” Its system returns to an optical approach, measuring antibodies, antigens, or DNA samples, but with a new twist: tiny LCDs inside its AmpCrystal system enable a “direct detection method” without signal or target amplification.
“We’re looking at wellness, infectious disease, chronic and acute infections initially where there’s a sense of urgency, not necessarily life and death in every case, but where the medical intervention would be changed dramatically to improve the results,” Campbell says.
UNIVERSAL SELECTION
For companies, developing a technology solely for use in clinical trials involves a degree of unpredictability even surpassing that of commercial development. Markets may be moving targets, but they are at least visible. In contrast, the aims, protocols, and support needs of clinical trials are only generally as predictable as trends in therapeutic areas or scientific knowledge. Often, the details of how a given trial needs to use diagnostics may be entirely unique — perhaps beyond any technology’s ability to customize.
Thus, even more than the market, clinical trials will tend to winnow down the players to the precious few that offer the most flexibility for drug developers. Short of building a new test from scratch for every trial — still the current practice in most cases — eventually the best individual solutions may prove to be the most universal ones.
PREACHING THE GLOBAL RMDx GOSPEL
Rapid mobile diagnostics may take root in the developing world before spreading to the developed world, according to Nanobiosym’s CEO Anita Goel. She says her company’s nanodiagnostics could be adopted by the developing world before the developed world. But the low cost and rapid results of such tests would presumably fuel parallel adoption of the technology in the leading global markets.
“It is important to start to see global health as a truly global phenomenon that’s an issue for both the developed and the developing world, and the solutions that cut costs in the developing world also cut costs in our developed worlds,” Goel says. “There are two big trends in medicine. One is the personalization of medicine, and the second is the mobilization of medicine, which is taking the ability to diagnose disease out of the centralized hospital or pathology lab, and bringing it out into the field — doctors’ offices, people’s homes, and even remote villages where they lack basic infrastructure.”
Nanobiosym’s website gives little information about the company or its “nanodiagnostics” technology, Gene-RADAR. Instead, it mainly serves as a link to Goel’s related public campaign and “global initiative,” the Nanobiosym Global EcoSystem. But the company has developed a platform technology on a dual track: mobile medicine and personalized medicine. The mobile medicine track focuses on the developing world and infectious diseases such as HIV, TB and malaria and could be adopted there first because of the lack of legacy healthcare infrastructure. The personalized medicine track focuses on the developed world markets and can be used as a companion diagnostic to cut the costs of clinical trials. Meanwhile, the company is building an “ecosystem of partners” for further development and refinement of its platform.
Goel believes RMDx technologies will evolve, eventually producing the contemporary equivalent of the “Star Trek” tricorder. Yes, a medical tricorder — now an official X-Prize target. Goel apparently inspired the new X-Prize initiative, and her company is one of the first entrants. Meanwhile, if you want to know more about the global network, you’ll have to join it (www.nanobiosym.com).
Not everyone sees such a close connection between the developed and developing worlds for RMDx, however. President Tony Eisenhut of developer Rheonix sees flaws in the concept. “Third world or developing world systems are usually focused on a specific disease, and most of those systems can only be brought to market at a low price point. When you look at putting systems in place in the developed world, where you may be running 5,000 to 50,000 tests a year, to make a large capital investment for a specific test is not feasible. There you want a system that has more of what they refer to in the molecular diagnostic business as menu. You want to be able to run more assays on a single piece of equipment as opposed to a special piece of equipment. Even if it’s low cost, there’s still maintenance and operator knowledge that goes along with it, and the healthcare industry wants to minimize that through our market feedback.”
RMDx: THE FDA’s VIEW
To get the FDA’s perspective on the future use of rapid mobile diagnostics in clinical trials, we spoke with Dr. Vicki-Seyfert-Margolis, the Commissioner’s senior adviser for regulatory science and innovation.
DO YOU BELIEVE RMDx TECHNOLOGIES CAN SPEED UP CLINICAL DRUG TRIALS AND FDA REVIEW BY IMPROVING PATIENT SELECTION AND MONITORING?
These devices could clearly have an advantage in the field, in particular in medical practice in the developing world, but it depends on the application and if it presents advantages over other tests that can be or are deployed in different clinical settings, particularly if there is no advantage in quality or accuracy. It is possible that these types of devices would allow more diffuse trials, i.e., that patients would not necessarily have to come to a medical center to be in a trial. This could be an advantage where people most appropriate for the trial are not able to travel, for whatever reason, e.g. economics, disability, location. Also, the “rapid” aspect of the device could benefit in allowing a patient to know right away whether they could enroll in a trial, and this probably has some value in more agile enrollment.
WHAT PROBLEMS OR CHALLENGES MIGHT HINDER THE USE OF RMDx IN CLINICAL TRIALS?
Depending on the accuracy, measures performed, and validity of the methods, there may or may not be an advantage to small mobile devices. It would be critical to see how these devices would or would not integrate into the overall management of the patient. For example, would they add significantly to the methods and diagnostic tests currently in use in a hospital setting, particularly if the tests are not as accurate?
If the device couldn’t do the right type of test in a valid way, then it wouldn’t be very useful in trials. We also like to see testing done in the same way as it would be deployed in the “real world setting.” So if the expectation was that if a rapid mobile device were to be a companion diagnostic, then we would want to know that physicians who were going to treat patients could use it. We often see some fundamental differences between test results when the technology is different.
(See also, “Speeding Up The Evolution Of Personalized Medicine,” June 2012.)
RMDx REGULATORY ROUTES
It is beyond the scope of this article to detail all the regulatory pathways that RMDx products and platforms might traverse. Although companion diagnostics grab all the attention these days, the use of Dx in clinical trials, involving a much larger variety of tests and technologies, has mainly proliferated off the radar, trial by trial. Pathways vary greatly, depending on each trial’s protocol, biomarker targets, patient sets, and so forth. And the regulatory authorities, like everyone else, are caught in the flux as the old wall between drugs and Dx devices wears away. Currently, diagnostic tests meant to replace similar assays or tests on the market go through the 510(K) route through the FDA. But tests for life-threatening diseases or with new applications or indications must obtain a premarketing approval (PMA), equivalent to the CE Marking designation in Europe. Some products may qualify for a CLIA (Clinical Laboratory Improvement Amendments of 1988) waiver from the FDA. But only simple tests that “use unprocessed specimens (whole blood or oral fluid), be easy to use, and have little risk of an incorrect result” because of good failure alerts, fail-safe mechanisms, traceable methods to ensure accuracy, and adequate labeling may obtain the waiver. Applying advanced Dx tests in clinical trials still requires close case-by-case collaboration with regulators.
The FDA publishes the In Vitro Companion Diagnostic Devices guidance, and it is now composing a draft guidance outlining strategies for clinical trial design and regulatory considerations for co-developing a novel companion diagnostic and therapy simultaneously. The draft guidance contains recommendations for the use of biomarkers for patient selection and screening, as well as clinical trial designs that allow ethical patient selection strategies. The FDA says it is also producing an “internal plan for how it will review applications using co-development strategies for product development to accompany both guidances and ensure the agency meets the special needs of these types of products in a timely way.”
The Center for Drug Evaluation and Research (CDER) has started a partnership program for qualification of new drug-development tools (DDTs). A company may apply to qualify a tool or a marker for clinical use, and if qualified, the tool will be put into the public domain. It can still be patented but must be shared. The company gains the ability to use the tool — say, a specific biomarker or other patient-rating instrument — in developing its products. An FDA guidance, “Qualification Process for Drug Development Tools,” furnishes the details of application, evaluation, and terms of the program.