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It's an incredibly tense race, and in its wake are literal and figurative trails of blood.
At stake? Three billion dollars in annual sales worldwide and a market base of 15.7 million people with diabetes who could experience fewer complications and less pain with more frequent blood glucose testing.
It's the decade-old noninvasive and semi-invasive blood glucose monitoring race, the race where hopes of manufacturers and people with diabetes run high, only to be periodically dashed and then rekindled.
With New Technology Come New Problems
Some of the developing monitors are designed to measure interstitial fluid (ISF). The fluid in the outermost layers of the skin, ISF flows underneath the outer skin layer and above where the nerve endings begin. The glucose in the ISF is actually the glucose that feeds the body's cells with energy to serve their purposes.
Withdrawing the ISF from the interstitial space above the nerve endings draws no blood and, say the manufacturers, causes little or no pain.
Some research studies conclude that ISF glucose measurements are accurate for diabetes glucose testing, but others say this has not been completely proven, and more research is necessary.
David Klonoff, MD, clinical professor of medicine at the University of California, San Francisco School of Medicine, however, offers a cautionary note on ISF glucose monitoring, saying it "has not been studied sufficiently for definite answers to be known."
Says Klonoff, most people agree that interstitial fluid and blood "contain essentially identical glucose concentrations, as long as the blood glucose levels are steady and not rising or falling."
The difference may be when glucose levels are rapidly falling or rising. He continues, "If the blood levels are rapidly changing, then interstitial fluid glucose levels may trail or possibly precede serum glucose levels."
If this lag time is true, people risk going hyper- or hypoglycemic without proper warning. If you are using an ISF monitor, your meter would tell you what your glucose level was 15 minutes ago, but not what it is at the moment you tested.
Companies who use ISF measurements counter with clinical studies saying that this lag time does not exist, or that it is only five minutes. Their studies have proven that ISF is accurate for home glucose monitoring.
The Food and Drug Administration
The FDA is responsible for verifying the safety and claims of the device manufacturers.
"One of the FDA's highest review items, even at the early stages, is noninvasive and semi-invasive glucose devices," says Steve Gutman, MD, director of the Center for Devices and Radiological Health at the FDA.
Glucose monitors fall under the medical device area of the FDA, for which companies must submit one of two possible applications. The first is the 510(k), which is for products that are "substantially equivalent" to other products already on the market, according to FDA spokesperson Sharon Snyder. The Premarket Approval Application, or PMA, is for breakthrough technology. The PMA carries many more detailed administrative requirements and will almost certainly take more time.
According to Gutman, the PMA, unlike the 510(k) requires a manufacturing section, an annual report, and a more detailed summary of safety and effectiveness. The scientific questions, though, are similar.
Bob Rosenthal of Futrex, a developer of noninvasive technology who has diabetes, calls the PMA requirements "so restrictive and expensive that it essentially stops any small company, and maybe even any large company, from obtaining FDA marketing clearance."
So far it appears that the FDA will be requiring the lengthier PMA for ISF measurement technology, ruling that the new glucose monitoring devices are not substantially equivalent to current market devices.
Rosenthal counters that the PMA requirements for noninvasive monitoring are much more stringent than those for finger stick devices. "We at Futrex believe that to impose these new restrictive requirements is a catastrophic disservice to the diabetic community," he states.
"We're not requiring the PMA; we're just suggesting it," says Gutman. "As we become more familiar with the technology that these companies are dealing with, we realize they're raising new issues related to safety and effectiveness that are really more readily addressed with a PMA than a 510(k)."
Few companies have approached the FDA yet, so just how often the FDA is saying no to a 510(k), and requiring a PMA, has not yet been tested.
First Through the FDA: Amira's "Alternate Site" System
One company, Amira, did get through recently with a 510(k).
The FDA approved Amira's AtLast Blood Glucose System for sale in December, after a 510(k) was submitted. Called an "alternate site" system, it measures blood glucose, not ISF glucose. It gets its blood from the forearm or thigh instead of the fingertips, which have a higher density of nerve endings.
The fact that no ISF measuring products have yet been approved is "indicative of the problems that interstitial fluid presents," says Joel Douglas, chief technology officer of Amira Medical.
Douglas can say these things because Amira has just won the semi-invasive race. Amira's review of the research says that ISF has not yet been proven effective enough for safe, at-home glucose monitoring.
How it gets its blood sample is not yet totally clear. Amira says "micro-components" draw blood painlessly, but will not further define what it is until later in 1999. After you lance the forearm or thigh, the sample is applied to a strip already inserted into the meter. From there, says Amira, a "capillary tube" transfers the blood to the meter for a number reading.
MiniMed Takes ISF Device to FDA
In late February, MiniMed submitted its ISF-measuring device to the FDA. Originally, MiniMed filed a 510(k) application, but in June it was converted to a PMA.
The invasive device consists of a catheter inserted into the abdominal area. This catheter has a sensor that measures the ISF glucose, and is connected by a wire to a pager-sized device that collects the glucose readings. This device stores readings inside, but has no screen to immediately give readings. It must be brought to a doctor, who can then download readings into a computer.
The patient must still use conventional devices to test BGs. One of these conventional readings is punched into the continuous device each day for calibration.
This continuous sensor does not allow a person to base insulin injections on immediate glucose readings, but MiniMed says it's an important step toward its goal of a semi-invasive home monitor.
Others in the Semi-Invasive Race: Integ
Integ's LifeGuide System consists of a handheld, battery-powered meter that measures the glucose level and displays the results. A single-use "key," similar to a very tiny needle, captures the ISF fluid sample.
Since development began, Integ has poured more than $37 million into the project. Still, before they can begin clinical testing, there is one more phase of development that must be completed, according to Susan Critzer, interim president: it needs a reliable measurement system.
"We need a way to read the information," says Critzer. "This is where we're stuck. Our measurement system isn't quite as precise as we would like it to be."
Integ plans to employ one of the two reading systems used in standard glucose meters: an electrochemical or a color metric system. The challenge is to take the ISF sample, introduce it to one of these systems, and come up with a way for them to translate it to a blood glucose number, which is what people with diabetes understand.
Mark Samuels, president and CEO of SpectRx, sees progress with his company's minimally invasive, hand-held Personal Glucose Monitoring System. The device uses a proprietary laser technology to create tiny micropores in the outer layer of the skin.
"The laser makes four to five holes the diameter of a human hair," says Samuels. "Then, a vacuum draws out the ISF which goes onto an assay strip which has been reconfigured to deal with ISF."
The one problem SpectRx is still faced with, according to Samuels, is getting a sufficient amount of ISF from all people.
"We can get it from 85 percent to 90 percent of people, but some conditions make it difficult to get it from the rest."
Samuels hopes their partnership and collaboration with Abbott Laboratories (makers of MediSense products), and the millions of dollars spent in research and development, will allow them to approach the FDA in 1999. Although he knows people would prefer a completely noninvasive device, Samuels says, noninvasive diagnostics using a light beam is too tough.
"Such a device will be in the market eventually, but probably not for 10 years or so."
TheraSense of Alameda, California, is working on two new blood glucose monitoring products. The first is a hand-held monitor designed to require only a tiny blood sample, one-tenth the size that current monitors require. It is called a "multisite" system, because it is designed to test the arm, thigh and abdomen, to help reduce or eliminate pain.
TheraSense is also working on a continuous glucose monitor, designed to provide alarms when glucose levels reach the hyper- or hypoglycemic range.
Several companies are working on a patch to measure ISF glucose. Through various methods, the patch makes "micro" holes in the skin. John Walsh, PA, CDE, is a diabetes author and a close observer of the industry, who has commented on the patch method. In a report entitled, "New Technologies in Testing," Walsh questions whether the "micro" holes from patches will irritate skin and possibly interfere with sample collection. He also wonders if sweating will change readings. The task of these patch developers will be to prove that no infection occurs when they go to the FDA.
Bioject + Elan = Marathon Medical
Bioject Medical Technologies of Portland, Oregon, and Elan Corporation of Dublin, Ireland, are working together on a semi-invasive monitor. The joint venture has taken the name of Marathon Medical, based in Boston.
Marathon's device is called the GlucoTrax System. A patch, placed on the navel area, uses "microprobe" technology to measure ISF glucose. The patch sensor is linked with a wrist-watch-type monitor that gives readings.
In January Cygnus reported it had begun the first step in the PMA process for the FDA. Cygnus' GlucoWatch is a semi-invasive device, yet a user still must perform two finger stick calibrations per day.
Cygnus' GlucoWatch looks like and is worn as a wrist watch. Attached to the watch is the AutoSensor, a transdermal patch that adheres to the skin. Using low level electrical currents, interstitial fluid is drawn into the patch and read by the GlucoWatch. Each patch is good for 12 hours of monitoring, but finger pricks are still needed to calibrate each new AutoSensor.
Craig Carlson, vice president for corporate marketing and strategic planning at Cygnus, says the company has completed its final developmental clinical study, although he will not yet release any data on that study.
Cygnus says the retail price should be around $225, plus the price of two AutoSensor pads per day, at about $4 each.
Technical Chemicals and Products Inc (TCPI)
TCPI thinks its submission to the FDA will come sometime in the fall of 1999, after completion of its current clinical trials.
The TD Glucose System uses a disposable skin patch about the size of a nickel that is placed on the forearm to measure ISF glucose. Once placed, you hit a button on an attached meter, which beeps about five minutes later when it has retrieved a glucose reading.
During that five minutes, a chemical reaction has occurred, changing the color of the patch, which the meter translates into a blood glucose number reading on the screen.
At the September 1998 Glucose Monitoring Developments Symposium, sponsored by the European Association for the Study of Diabetes, Jack Aronowitz, chairman, president, and chief executive officer of TCPI, explained the status of the TD Glucose System. According to Aronowitz, the transdermal patches used by the system are still handmade from materials that could withstand high-speed automation, thus indicating a potential for the device to be competitively priced. Company information says its current patch has a 98.37 percent correlation against blood glucose from the finger stick method, which puts it within acceptable FDA guidelines.
Companies employ one of four different technologies in the noninvasive race. The first two use radiation: near-infrared (NIR) spectroscopy (beaming in an outside light); and mid-infrared radiation spectroscopy (measures body heat). The third is passing a radio wave through the body to detect glucose. Finally, some use polarized light, which rotates in proportion to the amount of glucose in the body.
BioControl has created controversy here in the United States but has scored in Europe, where its noninvasive monitor is now available.
In September 1998, BioControl got its first European orders for the Diasensor 1000, which uses NIR technology. It sells for about 5,000 British pounds (approximately $9,000 U.S.).
But you can't buy it in American dollars, because it can't get by the FDA. It has twice refused approval for the Diasensor. Bruce Burlington, MD, former director of the FDA's Center for Devices and Radiological Health, said it was "too unreliable and unpredictable."
The European Union believes BioControl. One English distributor claims that, despite a steep price, he has sold some and hears that they are working successfully.
BioControl did not return phone calls from Diabetes Health to answer the question of exactly how many have been sold in Europe.
Another English distributor, Euro Surgical Limited of Guildford, England, says their customers are still in the lengthy "calibration process." It takes 60 days to calibrate the device, during which you must test with both a standard meter and the Diasensor, giving the Diasensor information about the specific user.
BioControl claims that during clinical trials, 80 percent of people did achieve successful calibration. Those who cannot get it to calibrate will get a refund.
Americans continue to wait for more information from across the Atlantic. On this side, BioControl will not say when it plans to go back to the FDA.
This Canadian firm has spent more than $8 million in developing the GlucoNIR noninvasive monitor.
Called a spectrophotometer, CME's instrument is the size of a briefcase. The finger is exposed to NIR light, then the information is transferred optically to a device that gives the reading using absorption to predict the blood glucose concentration. It can store readings, providing such information as trends and other statistical data.
In August 1998, CME severed its joint development programs with other biotech companies and, in November, appointed a new president.
Nonetheless, Jason Hogan, an investor relations specialist for CME, says they met with the FDA in December 1998 to discuss the protocol for the clinical trials to gather data for a submission. CME's clinical trials will be performed in an institution, like a nursing home, where health care professionals will use the GlucoNIR and standard glucose monitoring simultaneously on their patients. The two methods will be compared, and the data submitted to the FDA for approval.
Futrex has been working on the near-infrared Dream Beam since the early 1990s. Like many others, Futrex's major challenge is calibration. In its early years of development, the company's goal was a universally calibrated machine, meaning individual users would not have to do finger sticks to calibrate after purchase. Yet the company decided in 1995 that leaving universal calibration alone would ease its entrance onto the market.
Currently, Futrex is keeping quiet about its status in the noninvasive world.
Look out for the quiet ones.
Many companies need to talk about their progress often, to keep investors' money coming in. Instrumentation Metrics, a research and development company, keeps venture capital coming in without making lots of noise.
Besides its blood glucose testing system, Instrumentation Metrics is also developing noninvasive instrumentation for other types of testing.
Instrumentation Metrics won't say much about the device it wants to put on the market, but what they do say is that it is a portable, hand-held device using near-infrared light to measure blood glucose. The company has confirmed that they have had a number of meetings with the FDA.
This could be another quiet company that shocks the world with a big roar.
Some industry insiders believe that Rio Grande's device, another using near-infrared technology, will be one of the top finishers.
One of the researchers, Ries Robinson, of the University of New Mexico, said some time ago that he wants to keep quiet because he feels it is not fair to people with diabetes to hawk something that is just not there yet.
Keeping with this theory, Robinson did not return calls from Diabetes Health. Also refusing to comment was LifeScan, with whom Rio Grande is reported to be collaborating.
Korean corporate giant Samsung is developing the TouchTrak, which measures blood glucose with an electromagnetic radiant ray. It has not yet been cleared for sale yet in any country.
Samsung went to the FDA, but with only the handmade prototype, not a sample made from the company's production facilities. The FDA needs to see a few of the manufactured versions, to make sure that the company can mass-produce products with consistent accuracy.
Samsung says it is performing its own clinical trials both in Korea and in the United States.
What's the Hold Up?
There seem to be several reasons that noninvasive or semi-invasive glucose monitoring devices are not yet on the market.
Measuring the Glucose
Companies know where the glucose is in the body and how to get at it. The problem comes in how to evaluate that glucose in acceptable, reliable and valid ways. Companies using strips similar to those used by blood glucose meters must reconfigure the strip to work with ISF. Infrared readings need to be translated to something that corresponds with the current mg/dl readings. Regardless of the method used to collect it, ISF readings must be translated into blood equivalent numbers. This challenge faces all ISF devices.
The Business of Diabetes
Whoever wins this monitoring race stands to earn a ton of money, making themselves and their stockholders quite happy. The dream of winning, however, sometimes overshadows ethics, and lawsuits seem almost commonplace. The first company to submit an application to the FDA back in 1995, BioControl, apparently submitted a product that didn't work. A class action lawsuit against the company, filed in 1996, alleged falsified results and violations of federal securities laws.
BioControl isn't alone in the legal arena. TCPI was recently sued on a variety of counts, including patent infringement and unfair competition. Most of the counts have been dismissed by the courts, and TCPI expects those that remain to be disproved.
Futrex, another player in the noninvasive race, is still battling a 1996 Securities and Exchange Commission (SEC) charge of fraud, which may have something to do with the uncertain future of the device. The SEC claims that Futrex and its president, Robert Rosenthal, stated falsely that Futrex's hand-held Dream Beam analyzer could measure and accurately predict a person's blood glucose level by passing infrared light through a finger. However, according to the SEC, neither the Dream Beam nor any other infrared blood glucose analyzer tested by Futrex has ever been capable of predicting blood glucose levels accurately.
The Race Continues
Even with the current glitches, the hope builds again.
"What impresses me most in the area is the dazzling array of possibilty," says Steve Gutman. "There are lots of entrepreneurs and brilliant scientists with real hard work going on. I hope it's sooner than five to ten years."