The success of diabetes management technology leading to development of a closed-loop artificial pancreas will hinge on the incorporation of "intelligent" software than can adapt to individual patient needs, stakeholders say.

Diabetics must play an active, conscientious role in regulating their glucose levels and managing their overall health, which includes frequent finger sticks and insulin injections.

However, the advent of continuous glucose monitoring with FDA approval of Medtronic's Guardian RT system in August 2005 has provided patients with a wealth of information that previously was not immediately available to them (¹ Also see "Medtronic’s Guardian “Real-Time” Glucose Monitor Receives FDA Approval" - Medtech Insight, 15 August, 2005., p. 3).

Consisting of a small, disposable sensor inserted under the skin and a pager-sized monitor to which results are wirelessly transmitted, the Guardian RT system records blood sugar levels every five minutes and alerts patients of dangerously high or low glucose readings.

Abbott has projected that its FreeStyle Navigator continuous glucose monitoring system (CGMS) will receive FDA approval this summer. Approval for Johnson & Johnson/Animas' offering in this area, the GlucoWatch G3 , is expected in 2006, as well. Roche and DexCom also are developing CGMS (² Also see "Johnson & Johnson Snags Animas To Advance Artificial Pancreas Design" - Medtech Insight, 19 December, 2005., p. 3).

While diabetic patients still must use confirmatory finger-stick testing, those emerging systems have been perceived as a promising step in the direction of less invasive, more user-friendly diabetes care, in general, and an integrated insulin pump-glucose monitoring product, in particular.

Momentum for this goal is evident with FDA's inclusion of the "development of an artificial pancreas" as part of its 76-item critical opportunities list for medical product innovation, released March 16.

Accuracy Is At Issue For Future Developments

Sethu Reddy, MD, chair of Cleveland Clinic's endocrinology department, suggested in a March 16 interview that the rate at which diabetes management progresses toward an integrated system will depend significantly on the accuracy of glucose sensors such as that in Medtronic's Guardian RT system.

"There's a feeling that [the sensor] has to be 99.999% reliable," he said, "because if the wrong decision in terms of insulin injection is made on an inappropriate or incorrect blood sugar [reading]," it could result in serious complications.

To date, measurements from continuous monitoring products have not proved accurate enough on their own, and because finger-stick testing is still required, insurers have shown a reluctance to cover them, Reddy said.

Medtronic's limited launch of its Guardian RT system in seven major cities is designed to provide a platform for securing reimbursement in a challenging environment.

However, John Buse, MD, director of the Diabetes Care Center at the University of North Carolina School of Medicine and VP-medicine & science at the American Diabetes Association, said in an interview that he is confident "the continuous sensor is going to be revolutionary in the treatment of diabetes."

"Patients nowadays may get one reading a day [or] a handful of measurements a day. They have no clue how high their blood sugar gets multiple times a day, even when they're under good control, [or] how low their blood sugar gets multiple times a day," he said.

Closing The Loop: A Staged Approach

In its staged approach to bring an artificial pancreas to market, Medtronic plans next to develop a "semi-automated," or "open-loop" system, wherein glucose levels recorded by a sensor are used in a mathematical algorithm for the purpose of recommending an insulin dosage to the patient.

The patient and/or physician would still be responsible for making the final determination regarding insulin delivery. Medtronic says a system of this kind should be available in the U.S. in 12-18 months.

Ultimately, in a closed-loop system, data relayed from the sensor would be processed to automatically regulate insulin delivery, according to Medtronic.

A closed-loop system remains four to five years away, and will eventually be followed by a fully implantable version, the company says.

The key to these advancements, Medtronic suggests, is devising algorithms that take into account the wide variety of factors that might affect a patient's blood sugar level throughout the day - such as exercise, sleeping and eating habits.

Tama Donaldson, a spokesperson for Abbott, agreed about the importance of these algorithms in "accurately and reliably predict[ing] the insulin needs of a person with diabetes, much like a real pancreas."

Reddy likened the process by which algorithm-based software would "learn" the peculiarities of a patient to a baseball batter adjusting to a pitching style with increasing levels of success. "After a while [the batter] will recognize certain patterns [and] learn all the subtleties [and] hit most of the balls."

"Depending on how the patient is responding to the blood sugars, as well as the decisions the patient is making...the pump will learn in time how that individual person is behaving. And that's the challenge because one algorithm may not apply for every patient because everybody's a little different," Reddy noted.

Buse recognized the "huge advantages" to a closed-loop system. He added that "the challenge really is for [FDA] and these companies to decide how perfect a system you have to have."

"Everybody's afraid that one day an insulin pump and a glucose sensor would be like HAL in 2001: A Space Odyssey and decide they want to murder their owner. But my guess is that a reasonable system will [control blood sugar] much better than even the very best patients out there because it will be checking the blood sugar...a hundred or more times a day, so it has the capacity to self-correct," the doctor reasoned.

Wanted: Quicker-Acting Insulin

However, to move from a sensor and pump that "talk to each other with the patient sort of acting as referee" to a closed-loop system in which the patient's input is not needed at all, more rapidly acting insulin may be needed, Buse said.

Two different chemical analogs of insulin are now on the market - Eli Lilly's Humalog and Novo Nordisk's Novolog - that are labeled for an increased rate of absorption in the body. But Buse suggests more progress is needed in this area.

"The problem with our current kinds of insulin is you take a big slug of insulin [and] it may take three, four, sometimes more hours for that insulin to go away," he explained. "So the concern really is...if the sensor and the pump were to decide that the patient needed a few units of insulin - if they're wrong, the few units of insulin [are] going to be present for three or four hours."

"If we had more rapid-acting insulin it's just so much easier to have the pump turn on and off as soon as the blood sugar looks like it's rising [and] give you a little blip of insulin, then check your blood sugar five minutes later [and] if it still looks like it's rising then it gives you a bigger blip of insulin."

In addition to insulin analogues, new delivery systems could also make improvements in this area.

While most insulin delivery is done subcutaneously at present, intravenous delivery, for example, would allow insulin to get where it needs to go more quickly. However, implementing this approach carries with it a higher risk of blood clots, according to Buse.

Sensors that have intravenous access also would allow for improved performance.

With current devices that sample interstitial fluid "there's always about a 15- [or] 30-minute delay between what [is] happening in the blood and how it's reflected in the interstitial fluid," Reddy said.

"In other words your blood sugar can drop right now, for example, from let's say 100 to 60 in the next five minutes, and that may not show up in the interstitial fluid for another 30 minutes." Sensors that test intravenously could provide for real-time measurements, he said.

Medtronic says its future-generation Guardian technology will feature real-time glucose monitoring.

Both Reddy and Buse agree that Medtronic's timeline for introducing open- (12 to 18 months) and closed-loop (4 to 5 years) systems generally seem realistic, but it is harder to predict beyond that to an implantable system or even to the ultimate holy grail, a bioartificial pancreas made of living cells to more truly mimic the functioning of the insulin-secreting organ. Both of those systems are still a long way off, they say.

“Smart” Software Emerging As Key To Artificial Pancreas For Diabetes Care

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