The AJT Report: News and issues that affect organ and tissue transplantation

Abstract

An artificial pancreas that would automatically monitor and respond to blood glucose would be life altering for insulin-dependent diabetics. While past safety concerns have stalled FDA approval for clinical trials, development now appears to be progressing again. Also this month, a look at the surge in organ donor designations through the Facebook “Donate Life America” initiative.

Artificial Pancreas Within Reach

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[Initial artificial pancreas systems will be external devices combining a continuous glucose monitor and an insulin pump with a control algorithm to provide the right amount of insulin at the right time.]

Most patients with diabetes cannot achieve tight glucose control with traditional diabetes tools and spend only 30% of their days at healthy glucose levels, according to the JDRF (formerly the Juvenile Diabetes Research Foundation). Nighttime continues to be the most dangerous time.

The development of a closed-loop artificial pancreas device system (APDS) that automatically monitors insulin levels and delivers the vital hormone as needed would dramatically change the lives of insulin-dependent diabetics. Clinical trials are now under way, but the device probably won't be available for another three to five years.

In the meantime, an early version of an APDS—a low glucose suspend (LGS) system—is available and currently utilized by patients outside the U.S. This system monitors glucose levels and shuts off an externally worn insulin pump when sugar levels are dangerously low. However, the LGS system has not been approved by the U.S. Food and Drug Administration (FDA).

“We thought the FDA, in the past three to four years, was being too conservative” regarding LGS device approval, says Aaron Kowalski, PhD, assistant vice president of Treatment Therapies with the JDRF. As a result, the JDRF and others in the diabetes community have worked closely with the FDA in recent years to advance guidelines for LGS and APDS development. “We’ve seen impressive movement at the FDA over the last six to eight months,” he says. “The sense right now is that the FDA is really listening.”

The Path to an LGS Device

The JDRF, which traditionally had advocated biologic approaches to diabetes treatment, launched the Artificial Pancreas Project in 2005 to speed the development of commercially available, fully automated systems to maintain normal blood glucose levels. Commercial efforts also began. In 2009, the National Institutes of Health (NIH) funded multiple studies to accelerate the process. Over the next few years, several published studies have marked the progress.^1–3

The most promising approach in recent years is the LGS system. For example, a 2008 study funded by the JDRF and published in the New England Journal of Medicine found that people with type 1 diabetes who used LGS devices experienced significant improvements in blood sugar control.¹ In 2010, Bruce Buckingham, MD, professor of pediatrics/endocrinology and diabetes at Stanford School of Medicine in Stanford, Calif., and H. Peter Chase, MD, professor of pediatrics at the University of Colorado School of Medicine in Aurora, showed that more than 84% of overnight hypoglycemic events could be avoided by using algorithms that predict impending hypoglycemia and switch off the pump for 90 minutes.⁴

In a public hearing about two years ago, the JDRF and others in the diabetes community met with the FDA to express their concerns about the tremendous unmet need of diabetics and the potential of LGS systems. “The FDA said they were worried about some of the potential risks that go along with this system, such as ketoacidosis,” says Dr. Kowalski. However, “we countered that unrealistic large clinical trials would be needed—an incredibly difficult task—to demonstrate that this would not be a problem.”

Then, in June 2011, the FDA released proposed guidelines for an LGS system that many in the diabetes community found to be too cumbersome and unrealistic. As a result, the JDRF, the American Diabetes Association, the Endocrine Society, the American Association of Diabetes Educators and the American Association of Clinical Endocrinologists sent a letter to FDA Commissioner Margaret A. Hamburg, MD, stating they were concerned about the proposed guidelines and hoped the FDA would “issue guidance that will allow researchers, scientists and manufacturers to finally move forward with the next phase of outpatient clinical trials for the AP [artificial pancreas].”

KEY POINTS

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  The JDRF and others have worked closely with the FDA in recent years to advance guidelines for a low glucose suspend (LGS) system and artificial pancreas device system (APDS) development.
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  In late 2011, the FDA issued guidelines designed to speed up APDS development.
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  The JDRF expects a continuous glucose monitoring system to be approved by the FDA within a year, and an APDS within three to five years.

Development of an APDS

In December 2011, the FDA issued guidelines designed to speed up the development of an artificial pancreas system that were applauded by the diabetes community. The FDA's Charles Zimliki, PhD, said that equipment problems, computer glitches and problems with insulin used had hampered development of these systems.

The guidance recommends a three-phase clinical study progression so that studies may move to an outpatient setting as quickly as possible. “The FDA believes very strongly that an artificial pancreas device could be extremely useful for diabetics,” says the FDA's Stayce Beck, PhD, who is with the Center for Devices and Radiological Health. “We are working interactively with the investigators and companies in this field to help get their studies approved efficiently. In addition, we are prioritizing the review of such research protocol studies.”

Recently, the FDA approved the first outpatient study of a closed-loop APDS. The trials will be carried out by the University of Virginia in Charlottesville and the University of California in Santa Barbara; Montpellier University Hospital, France; and the Universities of Padova and Pavia in Italy.

What the Future May Hold

Dr. Kowalski at the JDRF says he expects a continuous glucose monitoring system to be approved by the FDA within a year. An APDS will take longer, probably three to five years, he says. “Ultimately, what we expect to see is something that restores some of the other hormones such as glucagon and amylin. A true artificial pancreas would try to restore the balance of multiple hormones,” he adds. “We’ll need new types of pumps that can pump more than one hormone and we’ll need these drugs approved for the pumps.”

Jon Odorico, MD, director of the University of Wisconsin Pancreas and Islet Transplant Program in Madison, says the current artificial pancreas technology is promising, and may provide a suitable solution for some patients. Being a simpler, less integrated technology than APDS, an LGS system is likely to get into the clinic first but, he says, “We will have to wait for the outcomes of the upcoming human trials in the outpatient setting, where important limitations of the systems such as compliance with recommended usage guidelines, accuracy compared to blood glucose levels during periods of rapid change, wireless signal interference, among others, can influence effectiveness and safety results.” After the initial trials it will also be important to compare the outcomes with those of pancreas and islet transplantation, which can achieve normalized blood glucose control without insulin and are the “gold standard” for preventing hypoglycemia, he adds.

Appendix

AN IDEA GONE VIRAL

DONATE LIFE AMERICA reported an initial “historic surge in online donor designations nationwide propelled by an initiative with Facebook.” Launched May 1 of this year, the initiative encouraged millions of Facebook users in the U.S. and United Kingdom to declare and share their organ donor status on their sites. In turn, the Facebook members were linked to their local state donor registry.

By the end of the first week following the announcement, 46 donor registries reported 33,406 online donor designations—more than 10 times the typical enrollment activity, according to Donate Life America. The organization plans to continue to follow up on the impact of Facebook.

Table 1.  Facebook/Donate Life America Online Donor Designation Activity During First Week of Initiative

State Donor Registry	Total Online Designated Donors	Percentage of Average
*Activity impacted by technical difficulties. **Includes Conn., Mass., N.H., R.I., and Vt. Source: Donate Life America
Alabama	62	1033%
Arizona	746	829%
Arkansas	67	1117%
California	4917	1171%
Colorado	386	1608%
D.C.	173	961%
Florida	2280	380%
Georgia	1012	5622%
Hawaii	22	367%
Idaho	62	1033%
Illinois	1186	2824%
Indiana	756	1400%
Iowa	856	2038%
Kansas	719	2397%
Kentucky	130	433%
Louisiana	407	2261%
Maryland	619	1032%
Michigan	1174	356%
Minnesota	899	3746%
Mississippi	328	1367%
Missouri	751	1788%
Montana	74	1233%
Nebraska	525	1458%
New Mexico	122	1017%
New York	1654	1622%
Nevada	242	2017%
North Carolina	1220	1130%
Ohio	697	465%
Oklahoma	320	2667%
Oregon	602	2508%
Pennsylvania*	58	322%
Puerto Rico	98	136%
South Carolina	398	1327%
Tennessee	281	781%
Texas	3224	896%
Utah	447	931%
Virginia	917	1698%
Washington	419	1397%
Wisconsin	1408	903%
Wyoming	43	717%
New England**	3105	2250%