The trend toward consumerism, the demand for portability, and the appeal of point-of-care IVD devices are all influencing detection technology.
In the field of detection technology, advances in multiplexing and the increasing emphasis on point of care are of primary importance. Trends include nonenzymatic and isothermal approaches for nucleic-acid testing, which reduce the complexity of very complicated molecular assays. The primary challenge right now is the front-end automation: sample acquisition and preparation.
To learn more about what’s new in detection technology, IVD Technology editor Richard Park spoke with John C. Carrano, PhD, president of Carrano Consulting LLC (Austin, TX). In this interview, Carrano discusses the major influences on detection technology, the latest trends in the field, and the challenges yet to be overcome.
IVD Technology: What have been the most significant advances in the area of detection technologies for IVDs during the past few years?
John Carrano: I believe that we’ve seen a substantial increase in multiplexing level by several of the FDA-compliant companies that are out there. And while that’s only one of a host of important attributes for an IVD technology, it certainly is particularly important, for at least three reasons: It improves specificity, applications are more broadly covered, and it reduces time, which means costs go down.
We also see in the literature new transduction and amplification modalities that are particularly well suited for point-of-care diagnostics, and the development of products for POC. To me that’s particularly exciting.
I find it very encouraging that we’re seeing some very novel ideas that are actually producing laboratory-quality results that appear to be suitable for a POC, low-complexity-type medical device diagnostic instrument.
And there have also been strides made in reducing the overall complexity of a device. In other words, taking the human out of the loop and making devices portable. There is a lot that’s being driven by the upstream part of things, or what I like to call “front-end automation.”
Why do you think there has been this increase in multiplexing?
I suppose everything is supply-and-demand driven at the end of the day, and that’s probably true for our business as well. There’s a demand for higher multiplexing level, and smart people have done a lot of hard work to try to figure out how to solve that problem.
And the reason for the demand is that, frankly, for all three of the attributes I just listed, those are areas where it helps everybody to make money. And making money is, in most cases, completely consistent with creating better health outcomes.
So when your specificity improves, then typically a clinician is able to make better decisions, get the answer right the first time. That’s good for the patient, it’s also good for everybody who is paying, because now we’re taking care of a problem one time and getting it right the first time. We do not need someone to come back in for multiple diagnoses, to be issued drugs multiple times because the first set of drugs was not really the right solution.
When I mention applications being more broadly covered, multiplexing allows someone to, for example, develop a respiratory panel that looks at things like flu, or atypical pneumonia, or metapneumovirus, or RSV-a whole host of things, and that has been a demand factor.
Additionally, anything that is done that is reducing costs of operation has got to be a good thing. I believe that’s what spurred the demand. The people that want to use this technology see it as a way to have a better product to offer; in other words, a better health outcome, and at the same time reduce their own costs. I believe that is the driving factor.
What are the latest trends in developing detection technologies for IVDs?
I think it is pretty well known that there has been some market progress made in nonenzymatic and isothermal approaches for nucleic-acid testing. And those are particularly intriguing because it’s a way to reduce what is otherwise a fairly complicated kind of assay, to run a molecular assay.
Molecular assays have numerous advantages, but specificity and sensitivity and being able to do very low-concentration analyte detection are certainly drivers for molecular approaches. And so the nonenzymatic and isothermal detection technologies and related amplification technologies are quite important.
We’re also seeing approaches that use signal amplification as opposed to more traditional target amplification. So rather than doing something like PCR, for example, in the case of a modular task, or instead of culturing or even incubating a pathogen for an immunological assay—rather than trying to make more of the target analytes that I’m looking for, these new approaches have thought of clever ways of taking what nature has given us and using signal amplification as part of the overall detection scheme, as a way of being able to get a valid detection, a valid diagnosis.
There is beginning to be real progress made now toward automating the front end, the upstream part of things. When we talk about detection technologies, we are not focused only on the transduction method; we are considering the device as a whole.
The upstream part is a huge challenge. Considerably less investment on the part of the government and on the part of companies has gone into that, and that’s really the problem that needs to be solved: the complexity needs to be taken out, and reliability needs to be put in, in order to see real dramatic changes in IVDs.
What are the primary challenges that IVD manufacturers encounter when developing detection technologies for their IVD products?
Like many businesses, ours is a very unforgiving one. You need to have excellent and reliable design, development, and manufacturing practices in place in order to succeed. Lacking those, you will fail. That failure might come later, or it might come sooner, but you will fail. That is particularly challenging for the new startups and for the smaller companies. It can even be a challenge for bigger companies that are not well run.
In many cases, these are companies that have been started by academics who might not necessarily have ISO manufacturing experience under their belts. They don’t necessarily have FDA QSR experience, or any regulatory experience, under their belts. They haven’t necessarily been through design transfer. They haven’t had to deal with those kinds of issues, and then all of a sudden they have to deal with them. I highlight it for smaller to mid-sized companies because that is where a lot of innovation is occurring, a lot of the most dramatic innovation.
Often we see larger companies buy these smaller companies. Why? Well, because the larger companies know that that’s where a lot of the most innovative work is taking place, and they are happy to leverage their risk by letting the new startups and the small venture-backed companies take the risk on their shoulders. Once the larger companies have seen some progress, they’ll acquire them.
If you want to be one of those successful smaller companies, and if we want to see success in innovation driven in our business, we’ve got to have these smaller companies that recognize right from the outset that business is an important part of their business. They need to understand that it isn’t just research, it isn’t just science and engineering. There is a tremendous amount that has to go into the mechanics of navigating a regulatory process, going through a sophisticated controlled design, development, and manufacturing process.
What role does sample prep play from a technology-development standpoint and as a challenge to technology development and R&D with regard to detection technologies?
I hate to trivialize things by saying, “Well, there’s one single most important problem that we must all solve.” Nevertheless, if someone forced me to pick the single toughest problem, so-called “sample preparation” would be it.
And that’s what I’m referring to when I talk about front-end automation. You know, that’s the sample acquisition, the preparation of the sample. It means I might have to do some filtering, some purification, some enrichment. There may be lysis or some other set of things that I have to do to that sample.
And then I have to do a bunch of processing steps in order to have this prepared sample, be able to run my assay, and work on my instruments. So I have all these different processing protocols that we would need to implement.
All of that I refer to as “front end.” That’s the upstream part. That is, to my mind, the single greatest challenge. It is also the area that has received the least amount of attention.
There is a lot of work in the literature that we read about. A lot of that work is nice, it’s great for publications, but honestly, I would say that much of what we see in the literature is going to just stay in the literature and not make itself into a manufacturing process. Part of that is because it’s not being put into a sophisticated FDA QSR–compliant design, development, and manufacturing system.
Back on the technical side, the technical challenge for sample prep is huge. I do think we are seeing the beginnings of some breakthroughs there, and I think companies that really take it to heart and recognize that it is the problem to solve are going to be the winners.
You said that sample prep is the most important factor, yet it’s received the least amount of attention. Why?
I believe there are a couple of reasons for that. First of all, my comment is predicated on a more global view that the biggest trend for IVDs is going to be in point-of-care diagnostics for infectious diseases.
And when I say “point of care,” I mean something that is truly low complexity that would be awarded a CLIA waiver. In other words, it would be suitable for use in a doctor’s office, in an ER, in an OR, in a clinic, in an urgent-care clinic, or in the rapidly growing clinical retail market. Or, it could be used by the government in security or operations, or in surveillance for pandemics at the point of need.
That’s what I mean by point of care. I want to be very clear about that. In other words, I would not need a laboratorian, I would not need any of the laboratory equipment: centrifuge, microscope, vortexer, liquid-handling robot, large system that needs to sit in an environmentally controlled room.
The sample-prep piece has become, in my mind, the preeminent challenge because it is the thing most lacking to make point of care happen. Now, if you’re someone who believes that the centralized model of laboratory testing will continue on for decades, then maybe what I’ve just said about sample prep is not true!
However, if you’re like me and you believe that the overwhelming trend is not just toward decentralization but is truly toward point-of-care diagnostics, then sample prep is preeminently important. So that is part of why it has not gotten much attention---because it is the disruptive innovation out there. It is the emerging thing.
Another reason it has not gotten a lot of attention is because many IVD manufacturers tend to be fairly risk-averse, and that is understandable. So this is not an area that they’ve necessarily wanted to try to invest in, because it wasn’t clear five or so years ago that point-of-care diagnostics and POC for infectious diseases really would be a huge market. But I believe it will, and I think others share that belief now.
And then the third reason is that, frankly, I think a lot of people just haven’t thought of sample prep as a real glamorous problem to solve. I’ve got a nanosphere, a nanodot, a nanowire, a nano this, a nano that, and that’s all wonderful. My background is in semiconductor device physics-I love that-but that’s not really the problem we have. It’s part, but it isn’t the biggest problem. The biggest problem is how do I get the sample, and how do I get it into a state that I can use it with all of these new and wonderful amplification and transduction modalities?
A fourth reason might be that the government has not paid much heed to sample prep. If you don’t have [inaudible] dollars out there that people can respond to, particularly these smaller companies, these newer startups, then those companies are not going to go off doing a research program that nobody seems to be interested in funding.
But I do believe that we’re seeing that trend begin to change. Another indication of a change there is that we are seeing quite a few conferences now that are popping up that are specifically in this area and that are specifically talking about it for point-of-care diagnostics.
How do IVD manufacturers overcome the “front end” challenges that you mentioned, and how do they go about making the detection technologies for their IVD products more sensitive and specific?
I think some companies do this right, and I think a whole lot of companies probably don’t. So let me tell you what I think is the right way to do it.
Clearly one right way is through M&A. There’s no doubt about that. You know, if you have a good business development team and you’re out there surveying what’s going on and you see opportunities to purchase or to license-maybe it’s just to license certain IP-then great. One way to overcome the challenges is to shop for the solutions.
If you’re trying to do it in house, my view is that you need to have a sort of a skunk work-a department tasked with advanced projects that is generally unhampered by bureaucracy-and you need to be willing as a company to put the R&D dollars into that skunk works. I used to be with the Defense Advance Research Projects Agency, DARPA, and I think a lot of these companies would be well served to create a DARPA within their own organizations-a group that’s a bit iconoclastic, that’s innovative, and that’s allowed to operate outside some of the normal boundary conditions.
But I would bind it by a condition that I like to call “disciplined creativity.” That might seem like a bit of an oxymoron, but essentially it’s a series of questions and steps that a good R&D organization can take early on to allow innovation to occur, that will, at the same time, force the innovators to recognize there has to be some element of discipline involved. There have to be certain questions that need to be addressed and answered in a rigorous, comprehensive manner.
The point I’m making is that companies need to invest in innovation. Appoint maybe five people to make up this DARPA group, or office, or department, that are acting as the ones who are looking to incubate and nurture the next disruptive technology that will help keep that company going for the long haul.
The approaches are, number one, you shop around for solutions to overcome the challenges. Number two is that you put a group like I’ve just described into place. That is, of course, hard to do when budgets are tight, and R&D always seems to be on the top of the list for an executive team to cut when you’re trying to meet some quarterly objective. But I think that is, in the long haul, a bit foolhardy.
What are the primary factors that IVD manufacturers take into consideration when deciding which detection technologies to implement and apply to their IVD products?
You have to be able to do rigorous analysis of opportunities. Using techniques like cost-benefit analysis and doing things like net-present-value calculations and analyses are very important.
Those need to be applied in a way that is still consistent with having the skunk works going on and trying to do something that’s really disruptive. But when you’re trying to figure out what the next technology leap should be, or how to jump off of the S curve and get on the next S curve, then I think you have to do some very rigorous analysis of what the projected opportunities are.
One additional comment I would make here is that when you’re considering something new in this space, you have to look out at least five years, because that’s about how long it’s going to take-even if things go great-for you to get an FDA-cleared medical device, an IVD, out on the market-particularly if you’re hoping to have the device CLIA waived, also.
If, right now, you’re saying, “Okay, here’s what’s happening in MRSA right now,” or “This is what’s happening in PCR technology right now,” that’s great, but you have to be willing to do that projection.
And frankly, companies that I consult for are often not doing this. Of course, many VCs don’t want to hear something like, “Well, we need to look five years out.” Because they’re not interested in getting their money out five years from now; they’d prefer to get it out a year or two from now. So this is a real tightrope to walk. It’s a difficult thing.
Do manufacturers ever establish partnerships or strategic alliances with other IVD manufacturers, research organizations, academic institutions, or universities to develop detection technologies for IVDs?
Of course; all the time. This is a critical part of the landscape. There is a tremendous amount of positioning and maneuvering and so forth going on in that regard, and that’s fine. That’s the nature of business, and it’s probably healthy.
This is compelling when you consider trying to, as a company, do something that is very transformative in nature. You need to try to leverage risk. You don’t want to completely expose yourself. So having a strategic alliance or working with a government lab, or FDA, or CDC, or getting a grant from the NIH is beneficial.
For large companies, a strategy might be to work with some smaller companies. All of these are opportunities to reduce exposure. It’s good for the smaller entity, it can be good for the lab or the institution that you’re partnering with, helping them get some research done. It can be good for the corporate partner in all of this in that they don’t have to go and directly expend huge resources to tap into what could be a breakthrough discovery.
How will the growth and evolution of molecular diagnostics continue to push the boundaries and demands of detection technologies for IVDs?
Molecular testing requires by its very nature more complex sample preparation. As a result of this, one would like to have a detection technology that is suitable for an upstream sample prep that minimizes the number and complexity of those upstream processing and preparation steps.
If you believe that ELISA techniques, for example, are the wave of the future (which I do not ), you might be less concerned about what you need to do with the sample prep and with the detection, the transduction and amplification approach.
But in the case of nucleic acid testing, molecular assays, and multiplexed molecular assays, figuring out assay formats and protocols such that sample-prep work is minimized would be very, very useful.
There’s a great challenge that exists in trying to interface different modules, if you will, that would be part of a system-level functional block diagram of an IVD platform. I like to refer to it as the impedance matching challenge, a metaphor to the electrical engineering-transmission-line classic problem.
And the metaphor is as follows: “Hey, I’ve got some sample prep that I’m doing, and I’ve got this great transduction amplification technique. Now how is it that the two of these things meet up properly?” That’s a big challenge, and I think molecular assays make that even more of a challenge-a less forgiving kind of challenge.
Do you have anything more to add about developing detection technologies for POC tests and the challenges involved in that area?
My global view is that point-of-care diagnostics is the single most important trend of this decade, and specifically POC for infectious disease. The reason I highlight infectious disease is because where POC will matter the most is for situations where time matters most, and getting a result quickly helps to improve the health outcome, and so infectious disease is that case.
It’s less likely that we’re going to see POC for cancer testing, for example, because I don’t know that there’s an economic driver or clinical driver that would say, “Here’s why we need to have this answer quickly and right at the bedside or right in the doctor’s office.”
I believe that POC testing is a subset of a much broader global megatrend, if you will, of applications at the point of need. Without getting us too far into philosophy, I think we see this and have seen this for a couple of decades all around us.
If you want to make a phone call, you just reach down and you pull out your cell phone. It’s right there where you need it. When you need cash, you go to an ATM. It’s another application at the point of need. And we don’t have to go back to our offices to get on our computers---we’ve got our laptops with Wi-Fi literally in our laps. There are countless examples like this. The point is that there is a huge trend of applications at the point of need. POC testing is part of that. That’s a good thing, because to me it shows that it’s part of an overall huge global movement.
I believe that point-of-care testing is going to be one of the things that will help take substantial cost out of the healthcare system. And regardless of your view on what kind of healthcare laws should or should not be in place, I think all of us would have to agree that if we had a way of yanking a lot of cost out of the system while at the same time providing better health outcomes, we would embrace that. POC testing gives us that opportunity.
We are also seeing now a trend in healthcare toward consumerism. In the Unites States alone there are more than 4500 urgent-care clinics. There are about 1500 retail clinics. These are full clinics that are in the big-box kind of stores-the Walgreens and Rite-Aids and Wal-Marts.
These clinics are set up so that you can just walk in and be seen by either a nurse practitioner or a physician’s assistant, or even a physician. And one of the most common things that is already being treated there is infectious disease. Clearly, if one had an excellent diagnostic tool that would allow the clinician to make a good decision, that would be a great thing and would take even more cost out of the system.
And, of course, one might imagine that it could even become a requirement on the part of insurance companies to demand such a test, because there is a conflict of interest if Walgreens says, “Oh, you’ve got a bacterial infection, and guess what? I happen to sell antibiotics right here. Let me sell them to you.” A good POC diagnostic test could reduce the likelihood of that, because the insurance company, before it pays for antibiotics, might want to see that the such-and-such test has been done that says, “Yes, this person has an atypical pneumonia, and it’s not Flu B, and that’s why we’re giving her an antibiotic.” Or, “It is Flu B, and that’s why I’m going to give him Tamiflu.”
So this is the megatrend, applications at the point of need, of which POC testing is a subset. Add to that the trend in healthcare toward consumerism, and, of course, the reality of our budget crisis and debt crisis, which will drive us to try to figure out ways to take costs out of the system while maintaining or even improving health outcomes. Those are the reasons why I put such a huge emphasis on point of care as the trend of the future.
What challenges will IVD manufacturers have to overcome in the future in developing detection technologies for their IVD products? And what new trends can we expect to see this year and in the future in the area of detection technologies for IVDs?
The single greatest challenge, I believe, is figuring out how to make a low-complexity front end. In other words, handling the sample-prep problem, as many of us like to call it, and as you referred to it. That is perhaps the single greatest challenge for IVD.
And, you know, with that come challenges and more technologies. How do you figure out which technologies? That’s why I say I think companies need to have a small skunk works that’s allowed to operate outside of company norms.
But that group needs discipline. I expect the trend toward consumerism in healthcare to grow, with a concomitant growth in POC technologies and products. The companies that determine how to solve the front-end automation challenge will be the winners in IVD in the coming decade.
John C. Carrano, PhD, is president, Carrano Consulting LLC (Austin, TX). Prior to starting his own consulting business, Carrano was the vice president, Research & Development at Luminex Corp. He also served as a corporate executive officer of Luminex, and chairman of the Scientific Advisory Board. Before joining Luminex, Carrano was as a program manager at DARPA for nearly 5 years, where he initiated and led several major Defense Department programs related to biological and chemical sensing. He can be reached at firstname.lastname@example.org.
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