In his SLAS2014 keynote address, Eric Topol, M.D., will provide a compelling perspective on the implications of "homo digitus" — a reference to the role of wireless physiological monitoring, genomics, imaging and health information technology to create "digitized" humans — for laboratory science and technology professionals working in life science R&D. "The whole way that we go about discovering and developing new drugs is going to be completely revamped," he asserts.
To say he is well known is to state the obvious. SLAS2014 keynoter Eric Topol, M.D., is a leading voice in the digital health care revolution, continually challenging the medical establishment to adopt technologies that will improve efficiency, lower costs and make treatments more effective. His credentials include, among others: director, Scripps Translational Science Institute; chief academic officer, Scripps Health; professor of genomics, Scripps Research Institute; senior consultant, Scripps Clinic, Division of Cardiovascular Diseases; and editor-in-chief of the online medical resource, Medscape. In 2012, he was named the Most Influential Physician Executive in Healthcare by Modern Healthcare magazine. He also was named one of 12 Rock Stars of Science by GQ magazine. Topol, a practicing cardiologist, is author or coauthor of more than 1,100 peer-reviewed articles and author of the book, The Creative Destruction of Medicine (Basic Books, 2012).
In The Creative Destruction of Medicine, Topol writes that pharma "has gone from a blockbuster to a busted model," and now is "an industry in peril." Its "hypo-innovative landscape" has led to consolidation rather than innovation—"coalescence" between companies, gobbling up of biotechs and generic drug manufacturers, as well as a spate of "joint venture marketing" efforts. "Where is the innovation to develop exciting new drugs and confront the real challenges of public health?" he asks.
Today, that innovation is starting to emerge. While far from ubiquitous, "a new model is beginning to take hold, and life science scientists have a role to play in driving that model forward," Topol says. "We're moving into a momentous phase in medicine, and every aspect of it will be affected. It's going to be a lot less of a ‘shot in the dark' and a lot more of a guided approach, informed by genomics. We'll also have biosensors to test much more precisely whether medicines are working in their desired, targeted way. This transformation calls for everyone in the field to take a new way of looking at what they're doing."
Topol has written and talked extensively and colorfully on the ways in which technology will allow patients to take control of their healthcare as never before (see Sidelines for selected links). In a commencement address at Rochester University, he told the audience, "Our cell phones are like pluripotent stem cells. We use them for our calculator, alarm clock, camera, video player and recorder, audio recorder, photo album, watch, flashlight—the list goes on and on. But now wirelessly connect the cell phone with biosensors in Band-Aids or wrist bands…[and] at any moment that you are using your phone—checking your e-mail, surfing the web—[you can also look] at the display of all your vital signs..."
In a presentation at the 2012 Consumer Electronics Show (CES), Topol introduced a number of "first-of-a-kind" devices. He used one, which enables a doctor to see a patient's electrocardiogram (ECG) on a smartphone, when a fellow passenger fell ill on a cross-country flight. The man complained of chest pains, and when someone called for a doctor, Topol pulled out his smartphone, snapped the heart monitor device onto the back of it and placed the man's fingers on the electrodes. He was able to tell by looking at the resulting ECG, displayed on his phone, that the man indeed was having a heart attack. The pilot made an emergency landing, and the passenger was treated and recovered.
Topol also showed the CES audience the rather large watch-like device that captures and displays the wearer's continuous beat-to-beat heart rhythm and blood pressure, oxygen saturation, respiratory rate and body temperature, among other vital signs (Topol is a member of the board of the device's manufacturer, Sotera Wireless). He also mentioned a device that monitors a person's glucose levels continuously and sends the information to a cell phone.
"At least a third of prescribed medications are wasted because people don't respond to them," Topol commented. That is likely to change, he noted, when a handheld genome analyzer, currently undergoing testing, becomes widely available. At that point, "you'll be able to go to the drug store, put a saliva specimen into the device and it will tell whether you will respond to the drug that's been prescribed for you or whether you should take another."
Also down the road, it may be possible to predict a week or two in advance whether you might have a heart attack. Topol and his Scripps colleagues have identified a gene signature for a heart attack. Using a nanosensor embedded in a person's finger, the team envisions detecting cells sloughing off arteries that could indicate an incipient heart attack. "The nanosensor would trigger an app that sends a ringtone to your phone alerting you that you will have a heart attack," Topol says. "Of course, that's one call you won't want to get."
What do all these new devices mean for bench scientists? "Work done in laboratories will become even more emphasized in the future because we will have lab-based insights about individuals that we couldn't have before," Topol says. "The input might be from a lab-on-a-chip or microfluidic device on an individual's smartphone, or it might be collected in a formal laboratory. Either way, everyone will have much more access to their own data—anything from their genotype to a cell-free plasma DNA of a tumor to all sorts of other information that we hadn't been able, previously, to incorporate into the daily practice of medicine or into the development of new therapies." SLAS members and their colleagues are contributing to the transformation of the health care landscape with an array of devices that are speeding both laboratory work and diagnostics. One recent addition detailed by JALA lead author Pak Kin Wong is a cell-phone-based microphotometric system that can assist in the management of multi-drug resistant infectious diseases in areas with limited resources.
On the drug development side, genomic information is now readily available, and should be used more widely from the very beginning to determine who will respond to a new drug and who won't, Topol urges. "For every drug that exists, there is a DNA interaction. Studies on those interactions should be done on every drug that is now commonly prescribed and for every new drug that is being developed," he emphasizes. "The biggest drug class in sales today is TNF inhibitors, which collectively will account for more than $30 billion in sales this year. Yet no work had been done before these drugs were commercialized to define who responds and who doesn't, and the result is that maybe 30 percent of people who take them respond. That translates into a total waste of $18 billion a year.
"Twelve new cancer drugs were approved by the FDA in 2012, 11 of which cost over $100,000 annually per patient," Topol continues. "If somebody is going to be taking such an expensive drug or biologic, you should want to guarantee that it works. That's something the development phase can take into account right now."
The anticoagulant Plavix (clopidogrel) is another example. This "blockbuster drug" is widely prescribed, "yet about 30 to 40 percent of people have no response to it because they have a loss-of-function gene variant that doesn't allow them to metabolize it," Topol says. "We can predict many of the genes that are in the pathways involved in this and other drugs. If you're going to make something like Plavix, wouldn't you want to make it preferentially for the people who can actually metabolize it? And, wouldn't it make sense to know this before you started the development program, so you would move it all the way through that way?"
Similarly, Pradaxa (dabagatrin)—the first new anticoagulant since Coumadin (warfarin) was introduced in 1954—came on the market in 2011. Shortly thereafter, according to Topol, data emerged showing a 30-40 percent reduction in major bleeding (a significant side effect of warfarin) among people with a common gene variant [CES1 gene single-nucleotide polymorphism (SNP) rs2244613] compared to those with the wild type gene. "I'm amazed this knowledge isn't used in practice because it means there is no reduction in efficacy but a marked improvement in safety in certain people taking this drug," he says. "Now there are three new blood thinners on the market, and this drug could have been—and could still be today—preferentially marketed because it has a decided advantage. This is a great example of how genomic data can be used to provide an individualized approach that ensures that a patient is protected, or at least quantitatively less at risk, for bleeding. And it could have been discovered before the drug ever came to market."
Until recently, the pharmaceutical industry has not been willing to incorporate this kind of testing during the discovery phase, Topol observes. "I believe we're in a transition now because now the industry is starting to realize that genomic data offers a remarkable opportunity to identify drugs that are going to be successful." In addition, in 2011, the US Food and Drug Administration issued regulations regarding the use of biomarkers in drug discovery/development in which it stated: "The use of biomarkers has the potential to facilitate the availability of safer and more effective drug or biotechnology products, to guide dose selection, and to enhance their benefit-risk profile." Therefore, the agency requires biomarker testing as part of the process of proving that a drug works for a particular disease on a specific subset of the population.
Why has pharma resisted taking a more individualized approach to drug development? "The resistance has been predicated on the concern that doing anything that's guided by genomics will segment the market," Topol explains. "But trying to find something that works in everyone is a recipe for trouble. By very precisely matching the intervention biologically with the individual, you get a whole new way of working, and products that have a much better chance of making a difference. That means discovery and development teams need to embrace a new mindset, which eventually will lead to a much higher rate of new drug approvals."
This new scenario means less emphasis on blockbuster drugs and more emphasis on drugs that provide efficacy based on assessments of people's biology and genes, according to Topol. "We'll also have the opportunity to learn about major side effects early on, before a drug goes to market, rather than learning after the fact about liver toxicity or heart attacks or other significant risks." He points to Vioxx as a drug "that could have been a big-time winner had the manufacturer invested in appropriate genomic data during the course of drug development. We wouldn't have had to learn after it was too late for many patients that one in 200 people who take it are going to have a heart attack or a stroke," he says. "We could have determined this problem long before the drug got into the clinic—and that's true for every drug that has been pulled from the market for similar problems.
"What's so different about today," Topol continues, "is that all these tools and capabilities—from next-generation sequencing to ultra-high-throughput genotyping to biosensors that can track any physiologic metric—are constantly being developed and are available as never before. So now the outlook from the life science industry is becoming enthusiastic or, at the very least, supportive."
Pharmaceutical company resistance is only one hurdle, however. Topol often cites a recent American Medical Association survey that found only 26 percent (about one in four) of physicians have had any type of education in pharmacogenomics, and only 10 percent currently believe they have the necessary information and training to put pharmacogenomics testing to use. In a journal article on the clinical relevance of pharmacogenomic testing, Topol and his colleagues summarize current tests and observe that "pharmacogenomic data will continue to accumulate, and the clinical utility of many other pharmacogenomic tests may be uncovered." They note that the FDA provides information on emerging pharmacogenomic tests in its online Table of Valid Genomic Biomarkers in the Context of Approved Drug Labels, which "includes boxed warnings, recommendations, research outcomes and relevant population genetics.
What about patients? Do many say they don't want to know what their genetic susceptibilities are, or do they resist using the emerging devices that will allow them to monitor their vital signs? "I've had patients, particularly older ones, about whom people might say, ‘they have to be the least data-driven people I'll ever meet,'" Topol acknowledges. "But when these patients start getting all this medical information about themselves on their phones, suddenly they become remarkably data-driven. So this idea that a large number people couldn't or wouldn't want that information, or couldn't handle it, really isn't true. The average person looks at his or her phone 150 times per day—and when that phone starts to have information about their health, not just about calories or how many steps they took, but about blood pressure, glucose or whatever the metric of interest is, things change quite a bit."
The devices that are available now and those that are currently in development are just the beginning, according to Topol, and there is plenty of room for innovation. "For these add-ons and apps to succeed, each one—and ultimately, all of them collectively—need to be reduced to a single screen that is easy to follow, attractive graphically and simple to use," he says. "That's falling into place for the individual apps—blood pressure, glucose, oxygen saturation and so forth. But the bigger challenge going forward is when we have to measure multiple indices. How will they be displayed on your cell phone or another dual device? How will you be alerted to share relevant data with your physician? That's the next tier of complexity in dealing with all the data."
Even now, "you cannot only get sensor information to a smartphone, but you can also incorporate a lab-on-a-chip add-on that measures metabolites, proteins—virtually anything," Topol enthuses. "So it's not just about sensor data or even DNA sequence data, but much more than that."
June 17, 2013