Transplant innovation and ethical challenges: What have we learned?

What does—and does not—spur innovation?

By Thomas E. Starzl, MD, PhD

LESSONS FROM THE CODMAN ANALYSIS OF FAILURES

Dr. Ernest Codman was a Harvard Medical School professor in the early 20th century who tried to introduce a system of analyzing failures at Massachusetts General Hospital and other Harvard-affiliated hospitals. As a result, he was metaphorically ridden out of town on a rail.

Codman recommended that complications and failures be classified as one of the following:

• An error in diagnosis
• An error in judgment
• An error in technique (if a surgical or a medicalproblem)
• An error in management.

Only one escape hatch existed that did not indictthe surgical or medical team as culpable: the disease. At the time, nothing could be done for many diseases, including cancer, heart disease, renal failure, and bowel insufficiency.

This is a type of analysis that can be brought to a mortality and morbidity conference and will not accept a lot of alibis; it forces the group to always look at what could have been done to prevent a complication or death. Some practitioners always want to blame some factor other than themselves: sometimes the patient, by being deemed noncompliant, is even held responsible for his or her own complication or death.

I think the Codman analysis of failures is a good starting point for discussing innovations, especially since true breakthroughs come in those cases where the failure falls into the category of being caused by the disease itself, not by a medical or surgical error. And that is surely where transplantation falls.

PROGRESS DOES NOT ALWAYS REQUIRE FULL UNDERSTANDING

Transplantation was first successfully performed in the context of breaking through the donor-recipient genetic barrier on January 6, 1959, when Joseph Murray and his team at the the Brigham Hospital performed a kidney transplant using the patient’s fraternal twin as a donor. This event was reproduced in Paris by Jean Hamburger and his team on June 14, 1959, and then on three or four other occasions in the next several years in patients who received sublethal total body irradiation. This was at a time when no pharmacological immunosuppression was available, so no follow-up treatment was offered.

Astoundingly, the first case—the fraternal twin— lived for more than 20 years, and the French case for 25 years, without ever being treated with immunosuppression. They were inexplicably tolerant. When immunosuppressive drugs were developed and survival rates improved, the questions around these early cases were never answered: Why did those transplantations work? What were the mechanisms of engraftment? What was the relationship of engraftment to tolerance? Without answering those questions, there was no way to make other big leaps in improvement of what was already proved in principle—that is, the feasibility of actually doing this kind of treatment. Improvements in patient and graft survival were dependent almost entirely on better drugs.

RANDOMIZED TRIALS HAVE A DUBIOUS RECORD IN TRANSPLANTATION

I know this will offend just about everyone here, but I have no confidence in evidence-based therapy if we are talking about randomized trials. None of the great advances in transplantation has had anything to do with randomized trials. In my opinion, randomized trials in transplantation have done nothing but confuse the issue and have very nearly made it impossible for the better immunosuppressants to be brought on board. Cyclosporine offered a tremendous step forward, but the randomized trials, carried out mostly in Europe, did not reveal much difference in outcome from treatment with azathioprine, at least as assessed by patient and graft survival. The same thing occurred when tacrolimus emerged; randomized multicenter trials actually delayed the widespread use of this superior drug for at least half a dozen years.

IN THE BIG PICTURE, MONEY IS HOBBLING INNOVATION

Earlier it was debated whether money drives everything. I do not believe that money drives everything in medicine in Europe, and it certainly has little to do with driving improvements in Asia. But money does drive everything in the United States, although the real question is whether it has to be that way.

I believe that innovation is somehow built within our genome. Many of the great advances in transplantation, the elucidation of principles, and the relatively recent discovery of the mechanisms of alloengraftment were achieved without grant support. The researchers involved could not have asked for National Institutes of Health funding because their ideas were so far out of the box that they probably would have been rejected or stolen.

I wonder to what extent the vast amount of money available for research is actually a disincentive for genuine advancements. Part of the problem is that the power of allocation is put in the hands of anonymous peer-review committees. That system generates droves of people to pursue money allocated to a certain area to learn more and more about less and less, in the vague hope that acquiring enough details will result in a realistic concept. Sometimes the picture simply becomes more confused.

Another problem is that we have produced far more scientists than jobs, so that funding becomes the first priority because it is the only means of employment. In earlier days, what drove people more often was that they were confronted with a child who was dying and the central questions was, “How can I treat this patient?” They did laboratory research on their own to produce evidence that a new innovative idea could work. I believe that if you have experiments that show that you can keep a heart beating on a preservation device for 12 hours, and you can put it in a dog and it works well, that is the evidence you need to proceed. How are you going to do a randomized trial—hang on to an organ and let it beat for 12 hours just so it conforms with some protocol? That is nonsense.

There was a period when clinical journals—Surgery of Gynecology and Obstetrics, Annals of Surgery, Annals of Internal Medicine, New England Journal of Medicine, and others—published front-running discoveries. That ended about 25 years ago when it became more important to learn about details. The journals then became superfluous, and for another reason as well: money drove the wheel more and more. Hospital and program administrators expected the publications to be advertisements, and the minute that articles started promoting something rather than reporting facts, they lost value. Today the impact factors of the surgical journals are at about 2 or 3, meaning that their articles are cited infrequently and have little real influence on the practice of medicine.

How did we reach this point where money drives everything? I think the page was turned in the very early 1990s, and it had to do with how medical practice is governed, especially in academic hospitals. Half of the health care in this country is now provided by hospitals that are associated with medical schools. Those hospitals and basic research laboratories are where our young people will assimilate their ideals. If that climate is not right, then we are raising the wrong kind of doctors.

Earlier researchers looked at a problem and thought, “Here’s a question that has to do with this patient before my eyes, and I must find some way to solve it. Let’s go to the laboratory.” Today there is a real danger that they are thinking, “I need to advance my career, so let’s see how I can get some money. A little research will be a stepping stone to my professional development.” Our discussion of medical and surgical ethics today should take place within this framework.