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June 11th, 2012
Last week surgeons, scientists and support staff from the the nation’s organ transplantation centers gathered in Boston for the annual American Transplant Congress. I attended to learn the latest news and because we were presenting two papers on the Islet Sheet.
Transplantation is a big medical business, the great majority of transplant procedures being kidney or liver replacement. My impression is that four-fifths of conference sessions were devoted to these two organs. Presentations range from organ acquisition, priming recipients for implant, the transplant surgery, immune suppression therapy, to managing complications and infections. This is important because these organ transplants can extend the lives of very ill people.
Islet transplantation is a minor organ transplant in total numbers but is very important to those of us with type 1 diabetes: it is as close as medical research has yet come to a cure. The total number performed to date is around a thousand. Over the decades islet transplantation has experienced waves of interest followed by busts and abandonment by many centers. The most recent milestone leading to increased islet transplants was the “Edmonton Protocol” announced in 2000. With this procedure, for the first time, the great majority of people treated required no injected insulin, sometimes for many years. Their glucose metabolism was normalized, at the cost of chronic immune suppression and its toxicity. Many centers set up or expanded clinical islet transplant programs in the wake of the Edmonton Protocol to repeat and extend Shapiro and Lakey’s work.
I am especially interested in islet transplantation because the Islet Sheet project is an attempt to make the benefits of islet transplantation available to everyone with the disease. At the conference there were around thirty posters and oral presentations on islet transplantation–around 2% of the total.
Now we are in a period of decline with fewer procedures, decreasing funding, and research centers discontinuing islet transplantation programs. Funding from JDRF has almost completely dried up. Probably the biggest setback is the failure to date to get FDA approval for islet transplantation, which is required for insurance reimbursement. A luncheon session devoted to the ongoing FDA study was illuminating with respect to reasons for the decline of islet transplantation during this cycle.
A large and complicated set of studies managed by NIH and FDA began in 2004. (It is worth noting that this time was the peak of the previous cycle, when scores of centers were replicating the Edmonton Protocol.) The key study is CIT-07 (Clinical Islet Transplantation Consortium protocol 7). The trial is prospective with a single treatment arm (meaning there is no control group in the trial). Forty-eight people were treated with one to three islet implants using islets prepared with uniform procedures. About half were insulin independent at one year.
The end point is (1) hemoglobin A1c at 1 year less than 7.0 and (2) greatly reduced hypoglycemia. (The FDA chose reduced hypoglycemia because insulin therapy is effective but tight control increases the risk of hypoglycemia; I think the FDA is right about this as an end point for islet transplant studies.) The last patient was treated in 2011, and the review and FDA approval are projected to be done in 2015.
One problem with the study is that the methods used, including the immune suppression regime, are already obsolete; better methods have been found. So when the CIT-07 protocol is approved no one will use it. Thus the original concept — an FDA approved protocol — has proven to be flawed.
A more serious problem emerged after the session. I chatted with one researcher who participated in the trial. He told me that the trial took so long, was so rigid, and had such burdensome reporting requirements that some of the clinical researchers are leaving the field in frustration. Thus a premature definitive clinical study on a procedure that remains fundamentally experimental has crippled the field.