As innovations in point-of-care testing gain steam, the regulatory landscape becomes more complicated.
Point-of-care testing is present---in varying degrees---in every hospital in the United States. Blood-glucose tests, pregnancy tests, and radiology-related tests, for example, are commonplace and virtually indispensible. Molecular diagnostics for infectious-disease testing are becoming more widespread as well.
With all of these technological advances come greater and more complicated regulatory scrutiny. FDA, CMS, and CDC are all keeping watchful eyes on the point-of-care testing market.
To learn more about what point-of-care test manufacturers need to know about this exciting and dynamic segment of the diagnostics market, IVD Technology editor Richard Park spoke with James H. Nichols, PhD, of Tufts University School of Medicine (Boston) and Baystate Health (Springfield, MA).
IVD Technology: What are currently the latest trends to emerge in point-of-care testing?
James Nichols: We’re seeing some trends in both the technology and regulatory environments. First, we are seeing more infectious-disease testing; particularly molecular. And in the regulations, there have been some changes to the interpretation of existing guidelines that have been made by both FDA and CMS.
Most recently, FDA is looking to tighten the criteria for approval of blood-glucose meters because many of the home meters migrated into hospital environments, or the technology that was applied to home meters migrated into the hospital platforms and began being used for intensive insulin management, which is a very different application.
So most recently, FDA has been tightening its criteria for agreement of a glucose meter against another comparative method. Previously, the accuracy had to be within plus or minus 20 percent. Now there is some debate as to what FDA will finally settle on. But it’s looking like plus or minus 15 percent, or 15 milligrams per deciliter, depending on the concentration range. It appears to be moving more toward the ISO guidelines’ criteria.
In CMS, there have been some changes recently in terms of tightening the criteria for operator competency. Previously there had been six criteria or categories for which you could evaluate operator competency-and the lab directors could pick which six were relevant for the testing methodology of their programs-now one has to evaluate operators on all six elements each year for moderate- and high-complexity testing.
So it’s not just direct observation. It’s also proving that these operators can report results, they can do maintenance. And the one requirement that’s catching a lot of people is that operators have to actually do a blind sample or a sample of known concentration as part of their annual competency.
This added testing is an expense, and with point of care it becomes complicated because samples aren’t really stable. You’re not collecting a lot of blood if it’s finger stick, so to do a duplicate test just to prove that someone is competent is a challenge.
There are also CMS changes to the interpretation of quality control for single-use devices like the cartridges used in blood gas analyzers. Previously, one could run quality control on a subset of the devices in an institution. You may have had twenty, thirty, fifty blood gas analyzers in use, but you would only have to run monthly quality control on a subset of those, and rotate the quality control each month on a different group of analyzers.
Now CMS is looking at quality control not by cartridge lot but by analytes. Regulators are asking for quality control to be performed by test: sodium, potassium. It doesn’t matter which cartridge you pick if there are different lots or configurations. You might now have to run sodium quality control once a month on each and every device that you’re using. So there is an added burden of cost that’s entering into the point-of-care realm.
CDC came out last fall with recommendations for infection control of point-of-care devices that may be shared among patients.
Unless one can dedicate a glucose meter for the length of time that that patient is staying in a hospital, you have to clean it between each use. The disinfectants take time because they are wet and have to dry on the surface of that device before the meter can be used again.
It becomes a challenge for nursing to test patients for insulin management before or during meal times. Now the nurses have that delay of eight to ten minutes between each patient test where they have to disinfect the device and wait for it to dry before they can go on to the next patient.
It is exciting to see the new technologies emerging, but then we’re also seeing increased regulations that are becoming challenging to meet.
How do IVD manufacturers reconcile FDA requirements with those of CMS and CDC?
That’s a good question. These regulatory bodies keep the IVD manufacturers on their toes, as much as the hospitals do. Much of the regulation is reactive. It’s not proactive. It’s reactive to complaints, to issues that have come out in the field. Take, for instance, the glucose meter. Because complaints are arising in the field regarding the use of glucose meters in the intensive insulin protocols, the agencies are asking, “Well, how do they perform in those protocols? Why did we let these devices be used in this fashion? We didn’t approve them for this use.”
CDC’s crackdown on infection control sprang from reports that came out a couple of years ago. There were several instances, primarily in nursing homes and long-term-care facilities, where, due to poor phlebotomy technique, Hepatitis B was spread among the patients. That was primarily because caregivers were using needle holders that were contaminated, even though the individual needles were sterile.
And then there was the question of whether that contamination spread to the meter itself, and the realization of the need for better infection control, especially considering the heightened awareness of MRSA and some of the other antibiotic-resistant organisms in hospitals.
Particularly with CMS, as it cracks down on operator competencies, we look at the waived testing and, in particular, some of the complaints and the ways that waived tests are being used and misused: Do the operators know what they are doing when they are using these devices? Have they read the package inserts? Are they competent to be doing the test? It’s reactive.
What have been the most significant technological advances and developments in point-of-care testing during the past few years?
It is molecular testing for infectious disease. Many of these point-of-care devices are not yet portable. They are bench top, but they are taking amplification technologies from several hours’ worth of time to achieve a result to producing a result from a whole blood sample in less than an hour.
This is tremendous that we have single-use cartridges that can do molecular types of detection methods away from the core laboratory without the use of separate rooms for isolation of DNA and for amplification. Here it is, all in one cartridge. It’s all self-contained, and you get the extraction, the amplification, everything from the native sample in less than an hour. That’s tremendous. And I think it’s only going to get better as we go on.
Would you say that the molecular-diagnostic point-of-care testing technologies are good and reliable and have reached a level where they are clinically effective and acceptable?
Yes. I’m not an expert in molecular diagnostics, but from the data that I have seen, point-of-care molecular diagnostics are very comparable to the molecular methods that would be used in a central laboratory. They’re just now capable of moving that technology out closer to the patient.
In terms of sensitivity, the number of organisms or copies of the organism are very comparable in terms of the sensitivities that they’re detecting. With molecular diagnostics, the specificity of the tests is determined by the probes that are utilized. And these specificities will only get better. I’ve seen some technologies that are looking at reducing the time from less than an hour to less than a half an hour. That goes to show that in the next couple of years we can expect things to get even better.
What are the primary obstacles IVD manufacturers encounter when developing their point-of-care testing technologies?
I can think of two main obstacles. The first is regulatory and getting the technology approved. There is a moving target for what is required for approval; particularly, for waived tests. The regulators seem to be going toward a more stringent type of protocol and process to grant approval for waived tests. That’s going to be one issue: getting approval to market it.
The second challenge for manufacturers is meeting consumer demand, and answering the questions, “Is the technology significantly better, more cost effective, leaner, more efficient? What’s the advantage for me to switch from the technology I’m already using to this new platform that’s coming out, and that’s always an obstacle in terms of marketing and selling it to the public-finding that niche?”
Obviously, if it’s a brand-new test that has never been done at the point of care, the first time it is done at the point of care, it markets itself. On the other hand, if it is your run-of-the-mill cardiac marker or pregnancy test, and there are a hundred other manufacturers that are doing the same test by different technologies, then you’ve got a lot of competition. You must determine what makes your product better than others.
These are all important things that IVD manufacturers have to look at: getting their technology approved, asking whether there is a market for it, and determining the market niche or that added advantage to the consumer.
Two points that you had raised earlier regarding point of care were the instability of patient samples and the issue of operator competency. How do these two factors pose particular challenges and obstacles to manufacturers and their point-of-care testing technologies?
Well, certainly if a test is easier to operate, you make fewer errors or it’s more foolproof, that is a device that consumers really want to jump on. Unfortunately, there is no perfect device. If it existed, everyone would be using it.
So certainly, if a device features easier operator training and is easier to use, with fewer errors; if it locks up when something goes wrong with the device, and it does everything automatically, that’s a better device than something that’s manual and complicated to use.
How manufacturers overcome some of these challenges is to engineer out many of the problems and issues that the general consumers are currently having with the products on the market.
How else do IVD manufacturers overcome these challenges that you mentioned?
They talk to their consumers. They talk to their clients. They find out what their challenges are, and they fix those issues in the next generation of the devices. The best thing that they can do is listen to their public.
I would like to return to the issue of operator competency. I think many of us are under the impression that for point-of-care testing, whether the device is used in a clinic, a physician’s office, or an emergency room, there is really no qualification, per se, to use it. Is this assumption correct?
No. I don’t believe there is any foolproof device. Any test, under certain conditions, can fail. So it’s important that staff, no matter who they are, no matter what their educational level, from doctors to nurses’ aides, be trained on whatever the test is that will be run.
In the hospital setting, a physician must go through a competency or a credentialing process with his or her institution, at the end of which, his or her chair signs off that the person is competent to perform various procedures. It’s a similar thing with any operator. If you don’t do a test frequently, or you have never done a test before, you can’t be expected to pick up a device and run with it and get the right result. You have to know how to apply the sample, what type of sample to collect, when to collect it at the right time in patient care. You also have to know the nuances and the ins and outs of that device. How does it store the reagents? How is maintenance on the device performed?
Even a device as seemingly simple as a glucose meter: you don’t expect that a general consumer with an eighth-grade education is going to walk into a pharmacy, pick up a glucose meter, and be able to operate it correctly, without reading the package insert. Yet that’s what happens a lot of the time as we get rushed in our day-to-day practices. Particularly in physician-office practices, there is more pressure from insurance companies to see more patients, and from hospitals to see more acute patients, and there isn’t that time spent on learning the new device and proving that you know what you’re doing.
Take a busy emergency room. Because it is a very temporary, high-pressure type of staffing in the emergency room, you don’t have much long-term staff that stay there for many years. Because of that high staff turnover, you’re constantly in this training mode, and if you don’t do a test frequently, if you only run Test X once per week, how can you expect 200 people to become competent on a test you only run weekly? You either limit the number of people who are doing that test or you just don’t do it in that environment and I think those are the issues that we deal with.
Even with the most simplistic of tests, unless the person performs it over and over again and becomes familiar with it, that person forgets how to do it the next time.
I’ll give you a real-life example: a rapid strep test. I went into a physician’s office several years ago with my daughter. My daughter was being tested for rapid strep, and the nurse wasn’t quite clear on how to perform the test. I suspected as much as she was looking at the kits when she opened up the package, and she had the swab, and she was looking at all the components. She collected the swab. I assume she did that right, but then she didn’t know how to apply it to the test, and she actually ended up inserting the sick side into the device, rather than the swab side, and I kind of had to sit there and shake my head and go, “Oh no. This is not going to be a good outcome here.”
That story illustrates how devices are not necessarily intuitive. So manufactures, to make a device intuitive, really have to work with the public, understand some of these issues, get out of the office, and go out to where the test is actually going to be deployed and learn some of these issues. Then they must go back to the drawing board and make the device as simple as possible, as foolproof as possible, where it’s obvious when you open the package that this is how it runs.
How does point-of-care testing, including diagnostic imaging, currently fit into the overall clinical diagnostic regimen at clinics and hospitals?
It’s huge. I think any application where the laboratory can’t get that test result fast enough has an application for point of care. And it used to be that point-of-care devices were only really useful for analytes that were quickly changing in the body, such as oxygen and glucose levels. Now, however, we are seeing analytes that are fairly stable, such as hemoglobin A1C, creatinine, tested at the point of care. There is demand out there to push that test, to obtain the result faster. For example, in radiology the clinician needs a test for renal function before giving radiopaque dyes to the patient. We use creatinine in our hematology oncology center mostly for dosing chemotherapy.
So when the patient comes in, if the pharmacist knows that person’s creatinine level, then the pharmacist can appropriately dose their medication. They can hang the IV bag, the patient gets the chemotherapy, and they go home.
Otherwise, they’re waiting for that test result, and that delays patient care. So having a creatinine test right at the time that they’re calculating the dose of that medication, can facilitate the whole pathway of care.
Any test that can facilitate those pathways of care, move the patient through the institution quicker, and improve patient-physician satisfaction are candidates for point-of-care tests.
Would you say we are at the point where point-of-care testing has become a standard or an essential part of the clinical diagnostic regimen at most major healthcare facilities and healthcare systems?
Absolutely. I would say glucose is virtually 100% saturated in every hospital you would go to in America because of the importance of monitoring for hyperglycemia, monitoring after surgery, reduction of infections. A variety of other tests, such as pregnancy tests, or those related to radiology or pre-surgery, are in nearly every hospital as well. I mentioned creatinine; certainly oxygenation in the intensive care units during follow-up after surgery or after accidents and trauma is widespread as well.
Point-of-care is here. It’s a big issue, and we need to manage it. We need to understand how we can better balance newer technologies as they come out, because there is constantly going to be a barrage of new point-of-care tests becoming available in the next several years.
How will such technological advances as wireless internet and tablet computers affect and push the boundaries of development in point-of-care testing?
Unfortunately, I believe that the IVD manufactures have missed the boat on this one. Particularly because we see waves of technology in the consumer world that don’t make it into our point-of-care devices and don’t make it into the instrumentation that we see in the laboratories, or even into the medical devices out on the floors.
We have yet to really get true wireless into a point-of-care device. We have wireless in the sense that it is in a carrier, and if you dock the device to the carrier and push a button, you can wirelessly send some communication-but that’s not like a cell phone.
Many of us are walking around with BlackBerrys and iPhones, and everything’s very automatic and transparent, and the testing devices just haven’t gotten there yet.
I would say we are easily ten years behind the technological advances that consumers have at their fingertips in terms of integrating those technologies into the point-of-care devices.
One reason for this may be the FDA approval process and the length of time it takes to validate, verify, and get approval for new devices through the system. But I think the other side of it is the hesitation of manufacturers to jump on a new technology if it doesn’t become the standard technology. Technology changes rapidly. If you don’t keep pace with the changes in technology, you get outdated.
So I think that many of the manufacturers of glucose meters and point-of-care devices, rather than jumping on the latest fad in technology, have taken a much more conservative approach and said, “Well, let’s wait and see which one becomes the standard, and then we’ll kind of work on it,” which places them three to five years behind the technology before it becomes the standard. And by the time they think about it becoming the standard, there is another technology coming out.
What I’d like is for my iPhone to do glucose testing, and to be able to read a urine dipstick on my iPhone, and to be able to read or scan pregnancy tests visually, and to be able to give me that result and store everything, and then send it wirelessly right through an iPhone or an iPad, and have it immediately available there.
Our physicians are certainly using smart phones and tablet computers. Out on the floors, they use them to order tests, they use them to look up results, they use them to review Institution Review Board protocols. We just don’t use them for testing yet.
I’m interested in your opinion that IVD manufacturers have, as you said, “missed the boat” on this subject. Please elaborate on that point.
The very slow adoption of new technologies is because of the time it takes to integrate these into the device, the money investment, and the length of time it will take before the manufacturer can actually recover any of the investment. That is problematic. I don’t think there is an easy answer for that.
Molecular Point-of-Care Testing
Is molecular point-of-care testing currently being used? Is it being accepted by physicians, and what is the attitude of reimbursement toward molecular diagnostic point-of-care testing?
I know that the menus that are out there are somewhat limited right now, but I believe MRSA was the first one to be available, and certainly there are hospitals that have adopted the technologies.
I don’t know what the latest is in terms of reimbursement, but certainly there is adoption of this. As the menus get wider, certainly the platforms are going to be more desirable because the more tests you can do on them, the more people will want them and see a use for molecular diagnostic point-of-care devices.
As we see them expand into respiratory viruses and into other types of needs, I certainly see molecular becoming the new wave-the next kind of technology after immunoassays.
What new trends can we expect to see this year and in the future in point-of-care testing technologies?
Imagination is the limit on this one. It takes a couple of years to develop the technology to a point that it’s ready to be integrated into a device, and then getting the device to market is a good three- to five-year cycle.
The things that we will see in the next year to two years or so are the things that were developed over the last five years. If we talk farther out, I think certainly where I see this going in the future would be enhanced fluidics-smaller sample size, splitting samples so you have one sample on many different tests-a more micro-type platform.
Certainly this type of array technology is being taken out to point-of-care multiplexing. In other words, what may have been done with DNA could also be done with immunoassay for cell markers, for other things.
I believe we are going to start to see many more hematology-type analyzers popping up. These will work on cell counters or flow-type analyzers.
Are there any clinical areas that you predict will see more point-of-care tests?
Yes. I believe the focus is on big disease states. It’s cardiology, it’s diabetes, and it’s infectious disease. Those are the three big ones.
And it’s not just another troponin. Certainly we now have high-sensitivity triponins that are making their way into the marketplace. But we are also looking for the new stroke marker and the new marker for catching the next H1N1 type of infection-these types of tests. But can the market respond quickly enough with the current platforms to detect those?
And if we have, for instance, molecular point-of-care diagnostics, given that it is only a new probe that needs to be made for these technologies, if the regulatory environment were right to allow the laboratory to take on the burden of determining validation and quality control on some of these, we might be able to respond to emerging types of infections in a more rapid fashion.
But that’s the balance between development on the manufacturer’s side and policy on the regulatory side.
Would you say that the developments in infectious-disease testing have been prompted over the past few years by the various flu pandemics that have emerged, such as Avian flu and H1N1? Did those pandemics divert resources or encourage people to rapidly develop technologies for infectious-disease point-of-care testing?
Certainly. I believe that anything that could help diagnose patients or differentiate populations of patients into various treatment regimens in a more rapid fashion, and improve outcomes, is going to drive that technology.
The faster you can get a test result that’s going to give you an answer that will to lead to a better outcome-that’s going to drive that technology.
What new challenges will IVD manufacturers have to overcome in the future in developing point-of-care testing technologies?
In addition to what we have discussed regarding infection control, ease-of-use for operators, and, in particular, getting the product through the approval process, quality control with these devices will pose challenges. Some of the new technologies are pushing the boundaries of what we consider traditional control processes. Traditionally we have bottles of reagents in our chemistry analyzers in the laboratory, and we do testing out of those bottles of reagents periodically to make sure that those reagents are still good.
We do two levels of liquid quality control once a day, and that would tell us if that bottle is still good on our analyzer until that bottle runs out, and then we’d run quality control on the next bottle when we opened it up, and periodically until we finished that bottle.
But now that we have single-use cassettes, we’re running quality control on that cassette. It uses up the whole test and you don’t know that the next cartridge is actually going to behave the same as the cartridge you ran the quality check on. How do you perform quality control on those cartridges?
You don’t. You quality-control the lot. You insert internal control processes from the manufacturer with each and every test. So this is a different strategy for running quality control that I think is going to challenge the regulatory process in terms of approval. The question becomes, Is this safe and effective when we put it in the hands of general users that don’t have a lot of laboratory experience?
The next wave is going to be the multiplex assays. Consider the DNA chip that may contain 500 different tests. Do you have to run two levels of quality control on each and every one of those 500 spots on that array? Or, is it sufficient to run a couple of process controls on this card and say that the card is working appropriately?
That question is open, and it’s still being debated. But of course there are certain processes for which it is physically impossible to test every aspect of a card, and this is going to come down to risk management. Incidentally, CLSI is now at the stage of approving the EP23 document, which is laboratory quality control based on risk management.
More and more it will be the laboratory directors determining what is effective in their settings for the way that they are using those test results, and the specific control processes for that device, as factors for how they will manage quality control. The balance between internal engineered control processes on the device and the liquid quality control that the laboratory is analyzing, plus the frequency of that quality control, is going to be the responsibility of the lab director more as this risk-based quality control gets implemented.
James H. Nichols, PhD, DABCC, FACB, is professor of pathology at Tufts University School of Medicine, and the medical director, clinical chemistry, at Baystate Health (Springfield, MA).